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United States Patent |
5,244,886
|
Scholz
,   et al.
|
September 14, 1993
|
11.beta.-phenyl-14.beta.H steroids
Abstract
New 11.beta.-phenyl-14.beta.H-steroids of general formula (I), where Z is
an oxygen atom or the hydroxyimino-grouping N.about.OH, and M and N are
either jointly a second compound or L is a hydrogen atom and M is an
.alpha.-permanent hydroxy group and either A and B together are a second
compound and D is a hydrogen atom, where R.sup.1 is a five or six-part
heteroalkyl residue or a cycloalkyl, cycloalkenyl or aryl residue or A is
a hydrogen atom and B and D together are a methylene bridge, where R.sup.1
besides the aforementioned residues may be a possibly substituted
hydrocarbon residue with up to 10 C atoms, a possibly substituted amino
group, a hydroxy or C.sub.1-8 alkoxy, mercapto or thioalkyl group, R.sup.2
is a methyl or ethyl residue, and R.sup.3 /R.sup.4 represents the usual
combination of substituents on the C17 atom in steroid chemistry, having
antigestagenic and other properties.
Inventors:
|
Scholz; Stefan (Berlin, DE);
Neef; Gunter (Berlin, DE);
Ottow; Eckhard (Berlin, DE);
Elger; Walter (Berlin, DE);
Beier; Sybille (Berlin, DE);
Chwalisz; Krzysztof (Berlin, DE)
|
Assignee:
|
Schering Aktiengesellschaft (Berlin und Bergkamen, DE)
|
Appl. No.:
|
663819 |
Filed:
|
March 20, 1991 |
PCT Filed:
|
September 20, 1989
|
PCT NO:
|
PCT/EP89/01090
|
371 Date:
|
March 20, 1991
|
102(e) Date:
|
March 20, 1991
|
PCT PUB.NO.:
|
WO90/03385 |
PCT PUB. Date:
|
April 5, 1990 |
Foreign Application Priority Data
Current U.S. Class: |
514/175; 514/176; 514/179; 514/180; 540/23; 540/41; 540/44; 540/47; 540/106; 540/107; 540/108; 540/114; 552/510; 552/511; 552/520; 552/540; 552/541; 552/544; 552/548; 552/553; 552/592; 552/593 |
Intern'l Class: |
C07J 043/0; C07J 051/00; C07J 041/00; C07J 019/00 |
Field of Search: |
514/175,176,179,180
552/511,520,540,541,544,548,510,593,592,553
540/41,44,47,23,108,106,107,114
|
References Cited
U.S. Patent Documents
4386085 | May., 1983 | Teutsch et al. | 514/176.
|
4954490 | Sep., 1990 | Cook et al. | 514/176.
|
Foreign Patent Documents |
57115 | Aug., 1982 | EP | 514/176.
|
116974 | Aug., 1984 | EP | 514/176.
|
129499 | Oct., 1984 | EP | 514/176.
|
277676 | Aug., 1988 | EP | 514/180.
|
283428 | Sep., 1989 | EP | 552/510.
|
881962 | Oct., 1988 | ZA | 552/510.
|
9014354 | Nov., 1990 | WO | 552/510.
|
Other References
Grant and Hackh's Chemical Dictionary (New York, McGraw-Hill Books, 1987)
p. 14.
|
Primary Examiner: Shah; Mukund J.
Assistant Examiner: Ward; E. C.
Attorney, Agent or Firm: Millen, White, Zelano & Branigan
Claims
We claim:
1. An 11.beta.-phenyl-14.beta.-H-steroid of formula I
##STR22##
wherein Z is O or a hydroxyimino group N.about.OH;
L and M either
together are an additional bond, or
L is H and M is .alpha.-OH; and
either
A and B together are an additional bond and D is H, and
R.sup.1 is
a) a heteroaryl radical of formula Ia
##STR23##
wherein A is N, O or S, and
B--D--E is C--C--C, N--C--C or C--N--C; or
b) a heteroaryl radical of formula Ib
##STR24##
wherein A is N, and
B--D--E is C--C--C, N--C--C, C--N--C or C--C--N; or
c) is cycloalkyl, cycloalkenyl or aryl radical Ic; or
A is H and B and D together are a methylene group bridging the C-10 atom of
the steroid skeleton and the ortho-carbon atom of the 11.beta.-phenyl
ring, and
Z is as defined above or is H,H, and
R.sup.1 is as defined above in a), b) or c) or is
d) a C.sub.1-10 -straight-chain, -branched, -saturated or -unsaturated
hydrocarbon radical Id, or
e)
##STR25##
wherein R' and R" are H or C.sub.1-4 -alkyl, or
R' and R" together with the N atom are a 5- or 6-membered heterocyclic
ring, optionally containing an additional heteroatom O, N or S in the
ring, or a corresponding tertiary N oxide or acid addition salt thereof;
or
f) OR"', wherein R"' is H or C.sub.1-8 -alkyl; or
g) SR.sup.IV, wherein R.sup.IV is R"'; or
h) a C.sub.1-10 -straight-chain, -branched, -saturated or -unsaturated
hydrocarbon radical substituted by one or more oxo, hydroxyimino,
C.sub.1-10 -alkanoyloxy or OR.sup.V groups, wherein R.sup.V is H or
C.sub.1-8 -alkyl;
wherein
any heteroaryl radical of formula Ia is optionally substituted by one or
more halogen radicals and/or one or more C.sub.1-2 -alkyl radicals, and
any cycloalkyl, cycloalkenyl or aryl radical 1c is optionally substituted
by one or more halogen, optionally protected hydroxy, alkoxy, optionally
in the form of the sulfoxide or sulfone and/or of the N oxide, oxidized
alkylthio and/or dialkylamino radicals;
R.sup.2 is a methyl or ethyl radical;
R.sup.3 and R.sup.4 are each, respectively
##STR26##
wherein R.sub.5 is H or a C.sub.1-4 -alkanoyl group,
Y is H, a Cl, I or Br atom, an alkyl, hydroxyalkyl, alkoxyalkyl or
alkanoyloxyalkyl group having 1-4 C atoms in the alkyl or alkanoyl
radical;
R.sub.6 is H, OH, or a C.sub.1-4 -alkyl, --O-alkyl, or --O-alkanoyl group;
O is 0, 1, 2 or 3;
R.sub.7 is a hydroxy or cyanide radical, or a C-.sub.1-4 -O-alkyl or
--O-alkanoyl group;
k is 0, 1 or 2;
Q is O or H,H.
2. A 13-alkylgonane of claim 1, wherein the heteroaryl radical of formula
Ia is a 3-thienyl, 3-furyl or 3-pyrrolyl radical.
3. A 13-alkylgonane of claim 1, wherein the heteroaryl radical of formula
Ib is a 3- or 4-pyridyl, 5-pyrimidine, 4-pyridazine or pyrazine radical.
4. A 13-alkylgonane of claim 1, wherein the cycloaryl, cycloalkenyl or aryl
radical Ic is a cyclohexyl, cyclohexenyl or phenyl radical.
5. A 13-alkylgonane of claim 1, wherein the alkenyl radical Id contains up
to three double bonds.
6. A 13-alkylgonane of claim 1, wherein the heteroaryl radical of formula
Ia is substituted by a Cl or Br atom.
7. A 13-alkylgonane of claim 1, wherein the heteroaryl radical of formula
Ia is substituted by a C.sub.1-3 -alkyl radical.
8. A 13-alkylgonane of claim 1, wherein the cycloalkyl, cycloalkenyl or
aryl radical Ic is substituted by one or two Cl and/or Br atoms.
9. A 13-alkylgonane of claim 1, wherein the cycloalkyl, cycloalkenyl or
aryl radical Ic is substituted by one or two optionally protected hydroxy
and/or C.sub.1-8 -alkoxy radicals.
10. A pharmaceutical preparation comprising an effective amount of a
13-alkylgonane of claim 1 and a pharmaceutically acceptable excipient.
11. A method of treating hormone-dependent tumors, comprising administering
an effective amount of a compound of claim 1.
12. A method of claim 11, wherein the hormone-dependent tumor contains
progesterone receptors.
13. A method of inducing abortion, comprising administering an effective
amount of a compound of claim 1.
14. A method of post-coital fertility control, comprising administering an
effective amount of a compound of claim 1.
15. A method of inducing menstruation, comprising administering an
effective amount of a compound of claim 1.
16. A method of inducing labor, comprising administering an effective
amount of a compound of claim 1.
Description
DESCRIPTION
This invention relates to 11beta-phenyl-14betaH steroids of general formula
I
##STR1##
in which
Z stands for an oxygen atom or the hydroxyimino grouping N OH as well as L
and M either together stand for a second bond or L for a hydrogen atom and
M for an alpha-position hydroxy group and either A and B together mean a
second bond and D means a hydrogen atom, and
R.sup.1 stands either
a) for a heteroaryl radical of formula Ia
##STR2##
and A=N, O or S and B-D-E mean the element sequence C--C--C--, N--C--C or
C--N--C, or
b) stands for a heteroaryl radical of formula Ib
##STR3##
and A=N and B-D-E mean the element sequence C--C--C--, N--C--C, C--N--C or
C--C--N or
c) stands for cycloalkyl, cycloalkenyl or aryl radical Ic
or else A means a hydrogen atom and B and D together mean a methylene group
bridging the C 10 atom of the steroid skeleton and the ortho-carbon atom
of the 11beta phenyl ring, and then
Z additionally stands for 2 hydrogen atoms and
R.sup.1 has the meaning indicated above in this claim under a), b) or c) or
d) stands for a straight-chain, branched, saturated or unsaturated
hydrocarbon radical with up to 10 carbon atoms or
e) stands for
##STR4##
with R' and R" meaning hydrogen or alkyl with 1 to 4 carbon atoms or R'
and R" with the inclusion of N meaning a saturated 5- or 6-membered ring,
and in the ring can contain another heteroatom such as O, N, S besides N,
as well as the corresponding tertiary N oxides and the acid addition salts
or
f) stands for OR"' with R"'=H, C.sub.1 -C.sub.8 alkyl or
g) stands for SR.sup.IV with R.sup.IV meaning R"' or
h) stands for a straight-chain, branched, saturated or unsaturated
hydrocarbon radical with up to 10 carbon atoms, which is substituted with
one or more oxo, hydroxyimino, C.sub.1 -C.sub.10 acyloxy or OR.sup.V
group(s) with R.sup.V meaning a hydrogen atom or a C.sub.1 -C.sub.8 alkyl
radical,
and optionally the heteroaryl radical of formula Ia is substituted by one
or more halogen radicals and/or one or more alkyl radicals with 1 to 3
carbon atoms
and cycloalkyl, cycloalkenyl or aryl radical Id is substituted by one or
more halogen, optionally protected hydroxy, alkoxy, optionally in the form
of the sulfoxide or sulfone and/or of the N oxide, oxidized alkylthio
and/or dialkylamino radicals,
R.sup.2 stands for a methyl or ethyl radical,
R.sup.3 /R.sup.4 stand for
##STR5##
with R.sub.5 meaning a hydrogen atom or acyl radical with 1 to 4 carbon
atoms
and Y means a hydrogen, chlorine, iodine or bromine atom, an alkyl,
hydroxyalkyl, alkoxyalkyl or acyloxyalkyl group with 1 to 4 carbon atoms
each in the alkyl or acyl radical
R.sub.6 stands for a hydrogen atom, a hydroxy group, an alkyl, O alkyl or O
acyl group with 1 to 4 carbon atoms each,
O stands for the numbers 0, 1, 2 or 3,
R.sub.7 stands for a hydroxy or cyanide radical, an O alkyl or an O acyl
group with 1 to 4 carbon atoms each,
k stands for the numbers 0, 1 or 2 and
Q stands for an oxygen atom or two hydrogen atoms.
As a special feature the compounds of this invention, deviating from
naturally occurring steroids, exhibit a beta-position hydrogen atom on the
14 carbon atom. Such 14beta H steroids have already recently become known
to a limited extent from European patent application 0 277 676. These
known compounds with .DELTA..sup.4,9 -3-keto steroid skeleton exhibit in
the 11 position a p-substituted (hetero)aryl ring. There are described as
p-substituents: optionally saturated or unsaturated, straight-chain or
branched hydrocarbon radicals with 1-10 carbon atoms, and the hydrocarbon
radical additionally can also carry a hydroximino, oxo and/or hydroxy
group of an amino group --NXY, with X and Y=H or C.sub.1 -C.sub.4 alkyl,
and if X and Y=alkyl, these, together with N, can also form a heterocyclic
3- to 7-ring.
The substitution pattern obtainable according to EP-A 0 277 676 on the
11beta phenyl ring is relatively limited. The search for other 14beta H
steroids, which exhibit substituents on the 11beta phenyl ring exceeding
EP-A 0 277 676, therefore seems urgently necessary to achieve compounds
which, for example, with regard to their antigestagen action, are superior
to those of EP-A 0 277 676.
The new compounds of general formula I as well as their pharmaceutically
compatible addition salts with acids are valuable pharmaceutical agents.
Thus, they have a strong affinity for the gestagen receptor and have
antigestagen properties.
The antiglucocorticoid effectiveness is just slightly pronounced or no
longer present at all (in comparison with the
11beta-(4-dimethylaminophenyl)-17beta-hydroxy-17alpha-(propin-1-yl)-4,9(10
)-estradien-3-one (RU 486) known from EP-A 0 057 115).
The affinity of the compounds according to the invention for the
counterreceptor is examined in the gestagen receptor binding test. Here
the displacement of the agonist by the antagonist is measured.
Cytosol from rabbit uterus homogenate, which contains the receptor
molecule--a protein--is used. The latter binds progesterone with great
affinity and little capacity. If these receptors are loaded with .sup.3 H
progesterone in the presence of the unlabeled substance to be tested, it
depends on the concentration and the binding affinity of the compound to
be examined, how strongly the .sup.3 H progesterone is displaced from the
receptor. After separation of the receptor-bound progesterone from the
unbound, the binding can be determined in percent and this value is
plotted against the logarithm of the molar concentration of the test
substance. Characteristic dose-dependent displacement curves are obtained
and now the concentration of the test substance that is necessary to
displace the reference substance completely from the receptor can be
determined. The competition factor K as a measurement for the binding
strength is defined as the ratio of the concentration of the test
substance to the concentration of the reference substance (progesterone),
at which both compounds show an equally great displacement of the .sup.3 H
progesterone from the progesterone-receptor complex.
TABLE 1
______________________________________
Gestagen Receptor Binding Test
Rabbit Uterus
Compound K (gestagen)
______________________________________
A 11.2
B 4.2
C 15
D 7
E 13
F 5.5
______________________________________
A=11beta-(4-acetylphenyl)-17alpha-hydroxy-17-(prop-1-inyl)-14beta-estra-4,9
-dien-3-one.
B=11beta-(4-acetylphenyl)-17alpha-hydroxy-17-(prop-2-inyl)-14beta-estra-4,9
-dien-3-one.
C=17-hydroxy-17beta-(3-hydroxypropyl)-11beta,19-(4-methoxy-o-phenylene)-14b
eta-androst-4-en-3-one.
D=17-hydroxy-17beta-(3-hydroxypropyl)-11beta,19-(4-(3-pyridyl)-o-phenylene]
-14beta-androst-4-en-3-one.
E=17-hydroxy-17beta-(3-hydroxypropyl)-11beta,19-(4-vinyl-o-phenylene)-14bet
a-androst-4-en-3-one.
F=11beta-(4-dimethylaminophenyl)-17alpha-hydroxy-17-(3-hydroxypropyl)-14bet
a-estra-4,9-dien-3-one. (comparison compound. EP-A 0 277 676).
Such active ingredients with antigestagen activity can be used first of all
for the treatment of hormone-dependent tumors that exhibit progesterone
receptors in their tissue. Preferred indication in this connection is the
treatment of breast cancer.
But they are also suitable for inducing abortions, since they displace from
the receptor the progesterone necessary for maintaining the pregnancy.
They can also be used for postcoital fertility control, inducing
menstruation and labor. Finally, they can also be used for treatment of
hormonal irregularities.
The antiproliterative potency of progesterone antagonists on the mammary
gland was determined in a bioassay. For this purpose, ovariectomized rats
were substituted for 3 days with estrone (10 micrograms) and progesterone
(3 mg) and another group at the same time was treated with the following
progesterone antagonists (1 mg/animal/day):
G:
11beta-(4-acetylphenyl)-17beta-hydroxy-17alpha-(1-propinyl)-4,9-estradien-
3-one,
H:
11beta-[4-(3-pyridyl)phenyl]-17alpha-hydroxy-17-(3-hydroxypropyl)-14beta-e
stra-4,9-dien-3-one,
I:
11beta-(4-dimethylaminophenyl)-4,5-dihydro-spiro[14beta-estra-4,9-diene-17
alpha,2'(3'H)-furan]-3-one (EP-A-0 277 676).
The entire inguinal mammary gland was dissected by performance of the
"whole mount" technique (Lyons and Johnson, 1952). Of six animals, the
number of tubulo-alveolar gland end pieces is determined by 40 times
magnification.
The antiproliterative potency is expressed in percent of the inhibition of
the tubulo-alveolar end pieces corresponding to the following formula:
(estrone (E)+progesterone (P))-(E+P+G)=100% of treated animals
(E+P)-(test compound H or I)=X%
100%-X%=% inhibition
G: 100 inhibition
H: 92% inhibition
I: 13% inhibition
TABLE 2
______________________________________
Antiglucocorticoid effectiveness of compounds A to G;
the effectiveness is indicated in % of th
effectiveness of RU 486
(effectiveness 100%)
Antiglucocorticoid effectiveness
Compound (in % of RU 486)
______________________________________
A 1
B 1
C 0
D 0
E 1
F 2
______________________________________
Thus the invention also relates to pharmaceutical agents on the basis of
pharmaceutically compatible--i.e., nontoxic in the doses used--compounds
of general formula I as well as their addition salts with pharmaceutically
compatible acids, optionally together with the usual auxiliary agents and
vehicles.
The compounds according to the invention and their salts can be processed
according to methods of galenical medicine known in the art into
pharmaceutical preparations for enteral, percutaneous, parenteral or local
application. They can be administered in the form of tablets, dragees, gel
capsules, granules, suppositories, implants, injectable sterile aqueous or
oily solutions, suspensions or emulsions, ointments, creams and gels.
In this case the active ingredient or ingredients can be mixed with
auxiliary agents usual in galenicals such as, e.g., gum arabic, talc,
starch, mannitol, methylcellulose, lactose, surfactants such as
Tweens.RTM. or Myrj.RTM., magnesium stearate, aqueous or nonaqueous
vehicles, paraffin derivatives, wetting, dispersing, emulsifying agents,
preservatives and flavors for taste correction (e.g., essential oils).
Thus, the invention also relates to pharmaceutical compositions, which
contain at least one compound according to the invention or one of its
pharmaceutically compatible addition salts with acids as active
ingredient.
Hydrochlorides and methane sulfonates can especially be mentioned as
addition salts of products with acids according to the invention.
A dosage unit contains about 1-100 mg of active ingredient(s).
The dosage of the compounds according to the invention in humans is about
1-1000 mg per day.
The 3-thienyl, 3-furyl and 3-pyrrol radicals are preferred of the possible
heteroaryl radicals according to formula Ia.
The 3- or 4-pyridyl, the 5-pyrimidine, 4-pyridazine or pyrazine radical are
especially suitable according to the invention as heteroaryl radicals of
formula 1b.
The cyclohexyl, the cyclohex-1-enyl, cyclohex-2-enyl, cyclohex-3-enyl as
well as the phenyl radical can be especially emphasized as cycloalkyl,
cycloalkenyl or aryl radical Ic.
The hydrocarbon radical according to formula I mentioned under d) or h) is
to exhibit in the unsaturated case preferably up to 3 double bonds.
Especially a chlorine or bromine atom can be mentioned as halogen
substituents, which are possible on the heteroaryl radical of formula Ia.
If the heteroaryl radical of formula Ia is alkyl substituted, the
monosubstitution is preferred.
The cyloalkyl, cycloalkenyl or aryl radical Ic can be substituted by one or
two chlorine and/or bromine atom(s). Said radicals can also be substituted
by one or two, optionally protected hydroxy and/or alkoxy radicals with 1
to 8 carbon atoms.
The alkyl groups with 1-4 carbon atoms occurring in
##STR6##
are preferably methyl, ethyl and/or propyl. If R' and R" together form,
with the inclusion of the nitrogen atom, a heterocyclic five or six ring,
which, besides N and C atoms, can additionally also contain an O or S
atom, there can be mentioned here the pyrrole, pyrrolidine, piperidine,
piperazine, morpholine, oxa and thiazolidine as well as thiadiazolidine
ring.
The methyl group is preferred as R.sup.2 substituent according to the
invention.
Of the combinations according to the invention possible for R.sup.3
/R.sup.4, none is to be especially emphasized, but the methyl, ethyl,
propyl or formyl, acetyl, propionyl as well as butyryl groups are
preferred for the alkyl and/or acyl groups occurring in R.sup.5, Y,
R.sup.6 and R.sup.7.
Two possible cases according to the invention can be distinguished relative
to substituents A, B and D.
1) A and B together form a second bond between carbon atoms 9 and 10, and D
stands for a hydrogen atom. The .DELTA..sup.4,9
-3-keto-11beta-phenyl-14beta-H-steroids of general formula I' are reached
##STR7##
R.sup.1 here stands, as already indicated, for a five- or six-membered
heteroaryl radical of formula Ia or Ib or for a cycloalkyl, cycloalkenyl
or aryl radical Ic.
2) A stands for a hydrogen atom and B and D form together a methylene group
bridging the C-10 atom and the O carbon atom of the 11beta phenyl ring.
The .DELTA..sup.4 -3-keto-19,11beta-o-phenylene-14beta-H-steroids of
general formula I" are reached
##STR8##
Additionally to the substituents already indicated under formula I' for
R.sup.1, R.sup.1 also stands for the substituents described in formula I
under d) to h).
Finally, both in formula I' and in I", L and M stand for a second bond
between the C-3 and C-4 atom or L stands for an H atom and M for an
alpha-position hydroxy group.
The new compounds of general formula I are produced according to the
invention, by a compound of general formula II
##STR9##
in which
A, B, D and R.sup.2 have the meaning indicated in formula I,
K means a blocked keto group in the form of the ketal or thioketal,
R.sup.1' either has the meaning indicated in R.sup.1 under a) to g), or a
straight-chain or branched, saturated or unsaturated alkyl radical with 1
to 10 carbon atoms, which contains the grouping
##STR10##
in the protected form
##STR11##
with K having the meaning indicated above or K means a hydrogen atom and
an optionally protected hydroxy group, as well as
R.sup.3' and R.sup.4' have the same meaning as R.sup.3 and R.sup.4 in
formula I, and present hydroxy and/or acyl and/or terminal alkyne groups
are optionally protected,
being subjected to the action of a dehydration agent, which is also capable
of releasing the 3-oxo group and the protected keto groups present in
R.sup.', optionally with formation of the 4(5) double bond, the resulting
product optionally being freed from other protecting groups and optionally
being reacted with hydroxylamine hydrochloride to the product of general
formula I with Z meaning the hydroxyimino grouping N.about.OH.
The release of the 3-keto function with simultaneous water cleavage and
formation of the 4(5) double bond takes place by treatment with acid or an
acid ion exchanger. The acid treatment takes place in a way known in the
art by the corresponding 5alpha-hydroxy-3-ketal being dissolved in a
water-miscible solvent, such as aqueous methanol, ethanol or acetone, and
by catalytic amounts of mineral or sulfonic acid, such as hydrochloric
acid, sulfuric acid, phosphoric acid, perchloric acid or p-toluenesulfonic
acid, or an organic acid such as acetic acid, acting on the solution until
the present protecting groups are removed and optionally water is cleaved.
The reaction, which takes place at temperatures from 0.degree. to
100.degree. C., can also be performed with an acid ion exchanger. The
course of the reaction can be followed with analytic methods, for example
by samples removed by thin-layer chromatography.
In general, protecting group removal and water cleavage are performed in
one reaction step, by the corresponding 5alpha-hydroxy-3-ketal or
5-en-ketal being reacted in a strongly acid medium for a certain time. But
it is possible equally well according to the invention for the protecting
group removal and water cleavage to be performed in two reaction steps
separate from one another, by the corresponding 5alpha-hydroxy-3-keto
compound first being recovered by a shorter treatment of the corresponding
5alpha-hydroxy-3-ketal in moderately acid medium and optionally being
isolated. The 5alpha-hydroxy-3-keto compound is then converted into the
3-keto-4-ene compound by allowing acid to continue to act with water
cleavage.
Various synthesis methods are possible for the production of the initial
products of general formula II. To achieve the compounds both of general
formulas II' and II" (by compounds of formulas II' and II" are to be
understood those that finally lead to the end compounds of formula I' or
the bridged compounds of formula I"), according to the invention the
synthesis indicated in the reaction scheme I below is suitable.
Production of the initial compounds of formula II is especially achieved
with the indicated, widely used process, in which R.sup.1' and/or
R.sup.3' and/or R.sup.4' can be substituents exhibiting one more C--C
multiple bonds, since they are introduced only after hydrogenation of
VII.fwdarw.VIII.
Production of starting compound III is described in EP-A-O 127 864; R.sup.2
and K have the meaning indicated in formula II.
By Grignard addition (Tetrahedron Letters 1979, 2051) of aryl halides
##STR12##
and 2-halogen aryl methyl halides
##STR13##
in which the addition products in the last mentioned case are still
subjected to a reductive cyclization reaction (Birch reduction with
Li/NH.sub.3 or reduction with Bu.sub.3 SnH), the compounds of general
formula IV are achieved (example 1; production of the initial compound).
##STR14##
Oxidation of the C-17 hydroxy to the 17-keto group (e.g., Oppenauer
oxidation) leads to compounds of general formula V.
The intermediate compounds of formula VI with an unsaturated D ring are
accessible, for example, by modified Saegusa oxidation [Tetrahedron 42
(1986) 2971] of the corresponding enol compounds of the 17-ketone. For
example, the trimethylsilylenol ether can be produced by conversion of the
17-ketone with lithium diisopropylamide in tetrahydrofuran to the
corresponding enolate and trapping by trimethylchlorosilane (Synthesis
1983, 1).
By basic treatment of VI, for example by stirring with basic aluminum oxide
or with silica gel/triethylamine in an inert solvent, the latter
rearranges into the corresponding steroid with beta-position 14H of
formula VII. The .DELTA..sup.15 double bond is subsequently again removed
by hydrogenation on palladium/activated carbon catalyst (10% Pd).
The introduction of the substituents R.sup.3' and R.sup.4' takes place,
after the usual process of the C-17 side chain synthesis, by nucleophilic
addition on the 17-ketone III and subsequent reactions ("Terpenoids and
Steroids," Specialist Periodical Report, The Chemical Society, London,
Vol. 1-12).
Introduction of the substituent --C.tbd.C--Y as R.sup.3', in which Y has
the meaning indicated above, takes place with the help of a compound of
general formula MC.tbd.C--Y', in which Y' is the radical Y protected with
a protecting group, such as, for example, trimethyl silyl or tert-butyl
dimethyl silyl, or else if Y is an alkyl group with 1-4 C atoms, Y' itself
is the radical Y.
The organometallic compound can also be formed in situ and be reacted with
the 17-ketone. Thus, for example, acetylene and an alkali metal,
especially potassium, sodium or lithium, in the presence of an alcohol or
in the presence of ammonia, can be allowed to act on the 17-ketone in a
suitable solvent. The alkali metal can also act in the form, for example,
of methyl or butyl lithium. Dialkyl ether, tetrahydrofuran, dioxane,
benzene and toluene are especially suitable as solvents.
The introduction of 3-hydroxy-propine, -propene or propane into the 17
position takes place by reaction of the 17-ketone with the dianion of
propargyl alcohol (3-hydroxypropine), for example, the dipotassium salt of
the propargyl alcohol generated in situ, to
17alpha-(3-hydroxyprop-1-inyl)-17beta-hydroxy derivative or with
metallized derivatives of 3-hydroxypropine, for example with
1-lithium-3-(tetrahydropyran-2'-yloxy)-prop-1-in-1-ide, to
17-[3-(tetrahydropyran-2'-yloxy)-prop-1-inyl]-17beta-hydroxy derivative,
which can then be hydrogenated to the 17-(3-hydroxypropyl or
hydroxypropenyl)-17beta-hydroxy compounds. This is achieved, for example,
by hydrogenation at room temperature and normal pressure in solvents such
as methanol, ethanol, propanol, tetrahydrofuran (THF) or ethyl acetate
with addition of noble metal catalysts such as platinum or palladium.
Introduction of homologous hydroxyalkyne, hydroxyalkene and hydroxyalkane
groups takes place in a corresponding way with homologs of the propargyl
alcohol.
The compound with the Z-configured double bond in the hydroxypropenyl group
is produced by hydrogenation of the acetylenic triple bond with a
deactivated noble metal catalyst (J. Fried, J. A. Edwards: Organic
Reactions in Steroid Chemistry, Van Nostrand Reinhold Company 1972, p.
134; and H. O. House: Modern Synthetic Reactions, 1972, p. 19). Suitable
as deactivated noble metal catalysts are, for example, 10% palladium on
barium sulfate in the presence of an amine or 5% palladium on calcium
carbonate with addition of lead(II) acetate. Hydrogenation is discontinued
after absorption of an equivalent of hydrogen.
The compound with the E-configured double bond in the hydroxypropenyl group
is produced by reduction of the acetylenic triple bond in a way known in
the art. A whole series of methods for conversion of alkines to
trans-olefins are described in the . literature, for example, the
reduction with sodium in liquid ammonia (J. Am. Chem. Soc. 63 (1941) 216)
with sodium amide in liquid ammonia (J. Chem. Soc. 1955, 3558), with
lithium in low molecular amines (J. A. Chem. Soc. 77 (1955) 3378), with
boranes (J. Am. Chem. Soc. 93 (1971) 3395 and 94 (1972) 6560), with
diiosbutylaluminum hydride and methyl lithium (J. Am. Chem. Soc. 89 (1967)
5085) and especially with lithiumaluminum hydride/alcoholate (J. Am. Chem.
Soc. 89 (1967) 4245). A further possibility is the reduction of the triple
bond with chromium(II) sulfate in the presence of water or
dimethylformamide in slightly acidic medium (J. Am. Chem. Soc. 86 (1964)
4358) as well as generally the reduction by action of transition metal
compounds with change of the oxidation stage.
Introduction of the hydroxyalkenes can also take place directly by addition
of a corresponding metallized hydroxyalkenyl compound, such as, for
example, 1-lithium-3-(tetrahydropyran-2'-yloxy)-prop-1(E)-ene (J. Org.
Chem. 40 2265) or 1-lithium-3-(tetrahydropyran-2'-yloxy)-prop-1(Z)-ene
(Synthesis 1981, 999). Homologs can also be introduced in this way.
Introduction of 3-hydroxy-propane as well as -butane in the 17 position can
also take place directly by reaction of the 17-ketone with metallized
derivatives of 3-halo-propanols or--butanols--in which the hydroxy group
in the metallization step is present as alcoholate (Tetrahedron Letters
1978, 3013) or as protected function (J. Org. Chem. 37, 1947)--to the
17-(3-hydroxypropyl)-17beta-hydroxy compound or to compound protected on
the terminal hydroxy group. Ethoxyethyl, tetrahydropyranyl and
methoxymethyl groups, for example, are suitable as protecting groups.
Synthesis of the 17-cyanomethyl side chain takes place in a way known in
the art from the 17-ketone, for example, by the 17-spiroepoxide and
cleavage of the spiroepoxide with HCN according to Z. Chem. 18 (1978)
259-260.
Also the introduction of the 17-hydroxyacetyl side chain takes place
according to methods known in the art, for example according to the
methods described in J. Org. Chem. 47 (1982), 2993-2995, Chem. Ber. 113
(1984), 1184 or U.S. Pat. No. 4,600,538.
If end products of formula I are desired with R.sup.3 /R.sup.4 meaning
##STR15##
the 17-(3-hydroxypropyl) compound is oxidized in a way known in the art,
for example, with Jones reagent, manganese dioxide, pyridinium dichromate,
pyridinium chlorochromate, chromic acid pyridine or Fetizon reagent silver
carbonate/Celite (Compt. rend. 267 [1968] 900).
Cyclization of the 17-(3-hydroxypropyl) or 17-(3-hydroxypropenyl) compounds
according to known processes yields the corresponding saturated or
unsaturated cyclic ether.
For the introduction of the groupings
##STR16##
the 17-ketone is converted with tosylmethyl isocyanide (Chem. Ind. 1972
213) to the 17-nitrile compound (Tetrahedron 31 (1975) 2151), which can be
converted directly with methyllithium or methylmagnesium bromide to the
17-acetyl compound, which yields the desired 17alpha-methyl-17beta-acyl
grouping after enolization with K-tert-butylate in tetrahydrofuran and
reaction with methyl iodide. This sequence of methyl addition on the
nitrile and then alkylation can also be performed in reverse order.
Present free hydroxy or hydroxy, mercapto and/or amino groups can be
alkylated or acylated in a way known in the art.
Sulfides and/or dialkylamines can be converted by suitable oxidation agents
(for example, hydrogen peroxide or peracids) to the desired sulfoxides
(n=1), N oxides (n=1) [see, e.g., Kontakte (Darmstadt) 1986,3, p. 12] or
sulfones (n=2).
Compounds with a dialkylamine substituent in R.sup.1' can be converted in
good yield to the corresponding (N-cyano-N-alkylaminoaryl) derivatives by
reaction with bromocyanogen in aprotic solvents such as, for example,
dioxane, benzene or toluene at elevated temperatures (amine decomposition
according to Braun) analogously to the instructions indicated, for
example, in Org. Reactions 7, 198 (1953), K. W. Bentley, Techniques of
Organic Chemistry 11, 773 (1963) and Houben-Weyl, 5/4 151 (1960).
The latter, depending on the ultimately desired meaning of R.sup.1 in the
end product, are reduced in a way known in the art to the corresponding
dialkylamino compounds (for example, with diisobutyaluminum hydride in
toluene to the N-formyl-N-alkylaminophenyl intermediate products and then
with lithiumaluminum hydride) or N--H--N-alkyl compounds (for example,
with lithiumaluminum hydride or with lithium in liquid ammonia). The
latter are then optionally acylated in a way known in the literature and
then optionally reduced to the new dialkylamino derivative in a way known
in the art, for example, with lithiumaluminum hydride (see DE 36 23 038).
As an example for a representative of the compounds of general formula IX,
the preparation of
3,3-(2,2-dimethyltrimethylenedioxy)-11beta,19-(4-methoxy-o-phenylene)-17-[
3-(tetrahydropyran-2-yloxy)-propyl]-14beta-androstane-5alpha,17alpha-diol
is described in example 1d).
By release of the protected hydroxy group and reaction with
perfluoroalkylsulfonic acid anhydride [alkyl with 1 to 4 carbon atoms; P.
J. Stang, M. Hanack and L. R. Subramanian, Synthesis 85 (1982)] the "key
compounds" of general formula XI (cf. also Example 1) are reached by
compounds of general formula X.
In the compounds of general formula XI, as described in EP-A 0 283 428 for
the analogous (bridged) 14alpha-H steroids, the trifluoroalkylsulfonic
acid initial group can be exchanged, to reach compounds of general formula
II, in which R.sup.1' has a meaning according to the invention other than
R.
In the conversion of the trifluoroalkylsulfonate compounds of formula XI to
compounds of formula II either the procedure is such that in a transition
metal catalyzed reaction (preferably Pd.sup.0) the perfluoroalkylsulfonate
starting group is displaced with essentially almost simultaneous
substitution by the desired substituent R.sup.1' or its precursor, for
example by allowing the reaction with tributylvinyl, tributylallyl or
tributyl-1-ethoxyvinyltin or with another trialkyltin derivative
containing the desired substituent (J. E. McMurry and S. Mohanraj,
Tetrahedron Letters, 24, No. 27, pp. 2723-2726, 1983; X. Lu and J. Zhu,
Communications, pp. 726-727, 1987; Q. Y. Chen and Z. Y. Yang, Tetrahedron
Letters 27, No. 10, pp. 1171-1174, 1986; S. Cacchi, P. G. Ciattini, E.
Morera and G. Ortar, Tetrahedron Letters, 27, No. 33, pp. 3931-3934, 1986;
A. M. Echavarren and J. K. Stille, J. Am. Chem. Soc. 1987, 109, pp.
5478-5486), or intermediately a corresponding triorganylstannyl,
preferably, tri-n-alkylstannyl compound, is produced from the
perfluoroalkylsulfonate compound [J. K. Stille, Angew. Chem. 98 (1986),
pp. 504-519). The latter is then transition metal catalyzed in a one-pot
reaction with a halogen, preferably bromine or iodine substituted
carbocyclic or heterocyclic aromatic substance [Y. Yamamoto, Y. Azuma, H.
Mitoh, Communications, pp. 564-565, 1986; T. J. Bailey, Tetrahedron
Letters, 27, No. 37, pp. 4407-4410, 1986], which optionally can carry
still other substituents, reacted to a compound of general formula II; the
phenyl radical exhibits in it the desired substitution or a precursor of
the desired substitution. The tri-n-alkylstannyl compounds (alkyl=butyl)
occurring intermediately, producible, for example, with hexabutylditin,
can optionally be isolated.
The compounds of formula II', but in which R.sup.1' then cannot stand for
a cycloalkenyl radical, are also reached by the reaction sequence
indicated below in reaction scheme II. Since a cycloalkenyl radical could
not survive undamaged the hydrogenation of XVI-XVII, the corresponding
11beta-(4-cycloalkenyl)-phenyl steroids cannot be produced in this way.
To illustrate the variant indicated in reaction scheme II, example 2
reproduces in a representative way the production of
17alpha-hydroxy-17-(I-propinyl)-11beta-[4-(2-thiazolyl)-phenyl]-14beta-est
ra-4,9-dien-3-one.
As another example for the rearrangement of a 14alpha-H steroid to the
corresponding 14beta-H steroid, example 3 shows the production of
11beta-(4-acetylphenyl)-17alpha-hydroxy-17-(1-propinyl)-14beta-estra-4,9-d
ien-3-one and from example 4 it can be seen by the preparation of
11beta-(4-acetylphenyl)-17alpha-hydroxy-17-(2-propinyl)-14beta-estra-4,9-d
ien-3-one how the 2-propinyl function is introduced as C-17 side chain.
##STR17##
To reach the bridged initial compounds of formula II", it is equally
possible--deviating from reaction scheme I--if the substituent standing
for the radical R is hydrogenation-stable (i.e., if the latter exhibits no
C--C multiple bonds), from a compound of formula IV"
##STR18##
by cleavage of the O methyl group [Tetrahedron Lett. 1327, (1970)] to
produce the free OH compound, to convert the latter with
trifluoromethanesulfonic acid anhydride to the corresponding
trifluoromethanesulfonate compound and then to functionalize the latter in
a desired way as already indicated in the 4 position of the o-phenylene
ring and only then to convert the 17-OH function, for example by Oppenauer
oxidation to the 17-keto function. A compound of general formula V" (cf.
EP-A 0 283 428) thus obtained
##STR19##
in which R.sup.1'a stands for all substituents indicated under R.sup.1',
with the exception of OR.sup.III, NR.sup.I R.sup.II and the hydrogenation
unstable substituents contained in R.sup.1' [hydrogenation conditions:
H.sub.2 normal pressure, Pd/C (10% Pd)], as already indicated, by
introduction of the .sup.15 double bond, basic rearrangement of the
14alpha-H into the 14beta-H compound and synthesis of the C-17 side
chains, is converted to a compound of general formula II.sup."a
##STR20##
The compounds of general formula I, with X meaning an oxygen atom, obtained
after protecting group cleavage and dehydration, can optionally be
converted, by reaction with hydroxylamine hydrochloride in the presence of
tertiary amines at temperatures between -20.degree. and +40.degree. C., to
the oximes (formula I with X meaning the hydroxyimino grouping N, OH, in
which the hydroxy group can be syn or anti position). Suitable tertiary
bases are, for example, trimethylamine, triethylamine, pyridine,
N,N-dimethylaminopyridine, 1,5-diazabicyclo[4.3.0]nonene-5 (DBN) and
1,5-diazabicyclo[5.4.0]undecene-5 (DBU), and pyridine is preferred.
For removal of the 3-oxo group for an end product of general formula I with
X meaning 2 hydrogen atoms, the directions indicated, e.g., in DOS 28 05
490 by thioketalization and then reductive cleavage can take place.
According to the invention it is also possible to functionalize the
compounds of general formula I even further to compounds which, in
comparison with those of formula I, then exhibit a modified B and/or A
ring.
There can be mentioned compounds which on the C6 atom of the steroid
skeleton carry a chlorine atom and/or a C.sub.1 -C.sub.4 alkyl radical
and/or on the C7 atom carry a C.sub.1 -C.sub.4 alkyl radical, compounds
which on the C6 atom carry two C.sub.1 -C.sub.4 alkyl radicals and
optionally on the C7 atom additionally carry a C.sub.1 -C.sub.4 alkyl
radical or else compounds which between the C6 and C7 atom exhibit a
second bond and optionally on the C6 atom carry a chlorine atom or a
C.sub.1 -C.sub.4 alkyl radical.
It is also possible to replace both H atoms on the C6 atom of a compound of
general formula I with a methylene or ethylene group, in which the C7 atom
additionally can exhibit the above-mentioned substitution.
If L and M in general formula I together stand for a second bond between C3
and C4, additionally the A ring of the steroid skeleton can be modified.
Then the C2 atom exhibits as substituent a hydrogen atom and a nitrile
radical or a C.sub.1 -C.sub.4 alkyl radical, a nitrile radical and a
C.sub.1 -C.sub.4 alkyl radical, two nitrile radicals, two C.sub.1 -C.sub.4
alkyl radicals or a methylene or ethylene group and/or the C1 atom a
C.sub.1 -C.sub.4 alkyl radical.
Also compounds with a second bond between the C1 and the C2 atom or with a
methylene bridge between the C1 and C2 atom, in which moreover in both
cases optionally a nitrile radical or a C.sub.1 -C.sub.4 alkyl radical is
on the C2 atom, can be produced from compounds of general formula I
optionally before or after modification of the B ring and belong to the
object of this invention.
Finally, it is also possible to introduce in the 2 or 3 position a radical
of the formula
##STR21##
Introduction of 1,2 and 6,7 double bonds, besides the 3,4 double bond, can
be performed according to known methods, for example, with dehydrogenation
agents such as selenium(IV) oxide, chloranil, thallium triacetate or
dichlorodicyanobenzoquinone (DDQ) or by allyl- or dieonolether bromation
and then hydrogen bromide cleavage [J. Fried, J. A. Edwards, Organic
Reactions in Steroid Chemistry, Van Nostrand Reinhold Company 1972, pp.
265-374, 1; Tetrahedron 42, (1986) 2971].
The allylbromation is performed, for example, with N-bromosuccinimide,
N-bromoacetamide, 1,3-dibromo-5,5-dimethylhydantoin or
dibromotetrachloroethane in the presence of a radical former such as
dibenzoyl peroxide in a solvent. Aprotic solvents such as dioxane and
chlorinated hydrocarbons such as, for example, carbon tetrachloride,
chloroform or tetrachloroethylene are suitable as solvents. The reaction
takes place between 0.degree. C. and the boiling point of the solvent.
The dienoletherbromation is performed, for example, analogously to the
directions in Steroids I, 233.
The hydrogen bromide cleavage with formation of the .DELTA..sup.6 double
bond takes place by heating the 6-bromine compound with basis agents,
preferably with lithium bromide and lithium carbonate or with lithium
bromide and calcium carbonate in an aprotic solvent such as
dimethylformamide at temperatures of 50.degree. to 120.degree. C. Another
possibility of the HBr cleavage consists in the 6-bromine compound being
heated in collidine or lutidine.
Starting from a saturated ring A, double bonds can be introduced in the 1,2
and 4,5 position at the same time, for example, by bromation to
2,4-dibromo-3-ketone and dehydrobromation of the dibromide with, for
example, lithium or calcium carbonate and lithium bromide in
dimethylformamide.
Introduction of a 6-methylene group can take place, for example, starting
from a 3-amino-3(4),5(6)-diene derivative by reaction with formalin in
alcoholic solution (Helv. Chim. Acta. 56 (1973) 2396) to the
6alpha-hydroxymethyl group and subsequent acid water cleavage, for
example, with hydrochloric acid in dioxane/water or starting from a
3-alkoxy-3(4),5(6)-diene derivative, analogously to the method described
in U.S. Pat. No. 4,544,555, or directly, starting from a 3-oxo-4(5)-ene
derivative, analogously to the directions in Synthesis (1982) 34.
Methylenation of 6-methylene to the 6,6-ethylene compound takes place with
dimethyl sulfoxonium methylide. For this purpose, the 6-methylene steroid
is added to a suspension of trimethyl sulfoxonium iodide with sodium
hydride in mineral oil and dimethyl sulfoxide or to a solution of
trimethyl sulfoxonium iodide and sodium hydroxide in dimethyl sulfoxide.
The reaction is ended after about 15 to 60 minutes at 20.degree. to
40.degree. C. [J. Am. Chem. Soc. 84 (1962) 866; European patent
application 0150157].
Introduction of a 2-methylene group takes place analogously to the method
of A. J. Manson and D. Woud [J. Org. Chem. 32 (1967) 3434] or the methods
cited there.
The methylenation of the 2-methylene to the 2,2-ethylene compound takes
place analogously to the methylenation of the 6-methylene compound [see
also Chem. Ber. 98 (1965) 1470].
Mono- or di-alkylated compounds in the 2-position can be obtained, for
example, analogously to the method of L. Nedelec, Tetrahedron 30 (1974)
3263.
Alkylated compounds in position 1 or 7 are obtained by 1,4- or 1,6-addition
on the corresponding enones according to known methods [J. Fried, J. A.
Edwards: Organic Reactions in Steroid Chemistry, Van Nostrand Reinhold
Company 1972, pp. 75 to 82, 2; and J. Am. Chem. Soc. 99 (1977) 1673].
Alkylated compounds in position 6 can be obtained, for example, by opening
of the corresponding 5alpha,6alpha-epoxides and subsequent reactions (J.
Fried, J. A. Edwards: Organic Reactions in Steroid Chemistry, Van Nostrand
Reinhold Company 1972, pp. 82-66. 2).
1alpha,2alpha,6alpha,7alpha,6beta,7beta-Methylene compounds or a
combination of the 1alpha,2alpha-methylene structure element with the two
6,7-methylene structure elements can be obtained by addition of
diazomethane or dimethyl sulfoxonium methylide on the corresponding enones
or by Simmons-Smith reaction [J. Fried, J. A. Edwards: Reactions in
Steroid Chemistry, Van Nostrand Reinhold Company 1972, pp. 100-126; Rev.
Soc. Quim. Soc. Mex. (1969) 171A; Chem. Ber. 101 (1968) 935; Chem. Ber. 99
(1966) 1118; Zeitschr. f. Naturf. 19b (1964) 944] of the corresponding
allylalcohols.
Production of isoxazole ring annellated on positions 2 and 3 takes place by
the synthesis of 2-hydroxymethylene compounds [Steroids 6 (1962) 178; J.
Am. Chem. Soc. 83 (1961) 1478] and their reaction with hydroxylamine [J.
Med. Chem. 6 (1963) 1].
[2,3-d]isoxazoles are also good starting materials for the synthesis of
2-cyano steroids [J. Med. Chem.6 (1963) 1].
Production of the pyrazole ring annellated on positions 2 and 3 takes place
by reaction of 2-hydroxymethylene-3-oxo feedstocks with R.sup.11
substituted hydrazine (U.S. Pat. No. 3,704,295).
Introduction of the chlorine or methyl substituent in C-6 of the steroid
skeleton is performed, e.g., by the methods indicated in German laid-open
specification 1 158 966 or in U.S. Pat. No. 4,544,555 and U.S. Pat. No.
4,196,203 by the corresponding 6,7-epoxides or 6-methylene derivatives as
well as by oxidation of the 6-chloro-3,5,-dienol ether with
dichlorodicyanobenzoquinone (DDQ) under acid conditions [Belgian patent
621,197 (1962)].
EXAMPLE 1
17-(3-Hydroxypropyl)-17alpha-hydroxy-11beta,19-(4-methoxy-o-phenylene)-14be
ta-androst-4-en-3-one (9)
a)
3,3-(2,2-Dimethyltrimethylenedioxy)-5alpha-hydroxy-11beta,19-(4-methoxy-o-
phenylene)-14-androsten-17-one (4)
9.50 g of
11beta,19-(4-methoxy-o-phenylene)-5alpha-hydroxy-3,3-(2,2-dimethyltrimethy
lenedioxy)-androstan-17-one (1) (production of this initial compound is
described following example 1) is instilled in a solution of 57.4 mmol of
lithiumdiisopropylamide in 200 ml of absolute tetrahydrofuran, dissolved
in 80 ml of absolute tetrahydrofuran, under protective gas at 0.degree. C.
Then chlorotrimethylsilane (13.8 ml) is instilled into the reaction
mixture. After stirring for 30 more minutes, the reaction solution is
poured onto ice-cold saturated sodium bicarbonate solution, the aqueous
phase is extracted with ethyl acetate and the organic phase is washed with
water and saturated ammonium chloride solution. After drying on sodium
sulfate, the organic phase is concentrated by evaporation in a vacuum.
10.8 g of
3,3-(2,2-dimethyltrimethylenedioxy)-11beta,19-(4-methoxy-o-phenylene)-17-t
rimethylsilyloxy-16-androsten-5alpha-ol (2) is isolated crude as yellowish
foam. This crude product is suspended in 127 ml of absolute acetonitrile
and mixed with 6.4 g of palladium(II) acetate. After stirring for 12 more
hours at room temperature, the reaction mixture is suctioned off over
Celite, the filter residue is rewashed with ethyl acetate, the filtrate is
concentrated by evaporation in a vacuum and the residue filtered over
silica gel (grain size 0.2-0.5 mm). After concentrationo by evaporation of
the filtrate, 7.1 g of
3,3-(2,2-dimethyltrimethylenedioxy)-5alpha-hydroxy-11beta,19-(4-methoxy-o-
phenylene)-15-androsten-17-one (3) is obtained crude as yellowish foam.
This crude product is dissolved in 2 l of a mixture of hexane/ethyl
acetate (1:9), mixed with 100 ml of triethylamine and then stirred for 12
hours in the presence of 500 g of silica gel. After filtration, it is
concentrated by evaporation and the residue is chromatographed on 800 g of
silica gel with a mixture of hexane/ethyl acetate/triethylamine (80:19:1).
There is obtained as the 1st fraction 3.47 g of above compound 4.
[.alpha.].sub.D.sup.22 =+40.8.degree. (C: 0.5, CHCl.sub.3).
As 2nd fraction, 2.41 g of a mixture (1:1 according to TLC) was eluted from
3 and the above compound 4.
b)
3,3-(2,2-Dimethyltrimethylenedioxy)-5alpha-hydroxy-11beta,19-(4-methoxy-o-
phenylene)-14beta-androstan- 7-one (6)
Under protective gas, 6.22 ml of diisopropylamine in 200 ml of absolute
tetrahydrofuran is taken at -10.degree. C. and mixed with 30.5 ml of a
1.6M n-butyllithium solution (hexane). It is stirred for another 30
minutes at -5.degree. C. and then 3.11 g of compound 4 prepared under a),
dissolved in 60 ml of absolute tetrahydrofuran, is instilled. The reaction
mixture is stirred for 15 minutes at -5.degree. C. and then is mixed by
instillation with 11.2 ml of trimethylchlorosilane. After 15 minutes, it
is cooled to -70.degree. C. and 5.4 ml of hydrogen fluoride-pyridine
complex is instilled. Then the reaction mixture is stirred for 2 hours
more at -60.degree. C. and then poured onto saturated sodium bicarbonate
solution. The aqueous phase is extracted with ethyl acetate, washed (NaCl
solution), dried on sodium sulfate and concentrated by evaporation in a
vacuum. 3.1 g of 3,3-(2,2-dimethyltrimethylenedioxy)-5alpha-hydroxy-
11beta,19-(4-methoxy-o-phenylene)-14beta-androst-15-en-17-one (5) is
obtained crude as yellowish foam. This crude product is dissolved in 200
ml of ethanol and hydroqenated with 369 mg of palladium/carbon (10% Pd).
Filtration over Celite and removal of the solvent in a vacuum yields,
after chromatography with hexane/ethyl acetate on silica gel, 2.18 g of
above compound 6.
[.alpha.].sub.D.sup.22 =+55.degree. (C: 0.51 CHCl.sub.3)
c)
3,3-(2,2-Dimethyltrimethylenedioxy)-11beta,19-(4-methoxy-o-phenylene)-17-[
3-(tetrahydropyran-2-yloxy)-1-propinyl]-14beta-androstane-5alpha,17alpha-di
ol (7)
The lithium organic compound is produced from 6.18 g of
3-(tetrahydropan-2-yloxy)-1-propine in 215 ml of absolute tetrahydrofuran
and 27.5 ml of a 1.6M solution of n-butyllithium (hexane) at -10.degree.
C. and a solution of 2.18 g of compound 6 obtained under b) in 45 ml of
absolute tetrahydrofuran is instilled in it at -10.degree. C. It is first
stirred for one hour at 0.degree. C., then overnight at room temperature.
It is poured into ice water and extracted with ethyl acetate. The crude
product is chromatographed on neutral aluminum oxide with hexane/ethyl
acetate. As main fraction 2.65 g of above compound 7 is obtained as white
foam.
d)
3,3-(2,2-Dimethyltrimethylenedioxy)-11beta,19-(4-methoxy-o-phenylene)-17-[
3-(tetrahydropyran-2-yloxy)-propyl]-14beta-androstane-5alpha,17alpha-diol
(8)
2.53 g of above compound 8 is obtained, after hydrogenation, as described
under b), from 2.65 g of compound 7, produced under c), in 150 ml of
ethanol and 265 mg of palladium/carbon (10% Pd).
2.53 g of compound 8, produced under d), is dissolved in 125 ml of acetone
and mixed with 6 ml of 4n hydrochloric acid. After stirring for 4 more
hours at room temperature, the reaction mixture is poured onto saturated
sodium bicarbonate solution and the aqueous phase is extracted with
methylene chloride. The combined organic phases are dried on sodium
sulfate and concentrated by evaporation in a vacuum. The residue is
chromatographed on silica gel. 1.16 g of title compound 9 is obtained.
[.alpha.].sub.D.sup.22 =82.6.degree. (C: 0.5 CHCl.sub.3).
f)
3,3-(2,2-Dimethyltrimethylenedioxy)-17-[3-(tetrahydropyran-2-yloxy)-propyl
]-11beta,19-(4-trifluoromethylsulfonyloxy-o-phenylene)-14beta-androstane-5a
lpha,17alpha-diol (11)
2 g of methoxy compound 8 produced according to example 1d) is dissolved in
31 ml of absolute dimethylformamide and mixed with 658 m of sodium methane
thiolate under protective gas. The reaction mixture is refluxed for 3
hours, then cooled to room temperature and then poured onto 200 ml of ice
water. It is stirred at room temperature until the crude product
flocculates as solid substance. Then it is suctioned off and dried in a
vacuum. 1.90 of
3,3-(2,2-dimethyltrimethylenedioxy)-11beta,19-(4-hydroxy-o-phenylene)-17-[
3-(tetrahydropyran-2-yloxy)-propyl]-14beta-androstane-5alpha,17alpha-diol
(10) is obtained crude. This crude product is dissolved in 45 ml of
absolute methylene chloride and mixed with 2.04 g of
4-dimethylaminopyridine. The solution is cooled to -70.degree. C. under
protective gas and slowly mixed, by instillation, with 0.7 ml of
trifluoromethanesulfonic acid anhydride dissolved in 6 ml of absolute
methylene chloride. After stirring for 1 more hour at -60.degree. C. the
reaction mixture is poured onto saturated sodium bicarbonate solution and
the aqueous phase is extracted with methylene chloride. The combined
organic phases are washed with saturated sodium chloride solution, dried
on sodium sulfate and concentrated by evaporation in a vacuum. After
chromatography of the residue on silica gel, 1.73 g of above compound 11
is obtained as yellowish foam.
IR (KBr): 1210 and 1420 cm.sup.-1 of triflate.
Production of Initial Compound (1)
11beta,19
(4-Methoxy-o-phenylene)-5alpha-hydroxy-3,3-(2,2-dimethyltrimethylenedioxy)
-androstan-17-one
a)
19-(4-Methoxy-2-chlorophenyl)-3,3-(2,2-dimethyltrimethylenedioxy)-9(11)-an
drostene-5alpha,17beta-diol
5.4 g of magnesium chips in 45 ml of absolute diethyl ether under
protective gas at room temperature is taken and mixed first with 0.55 ml
of 2-chloro-5-methoxybenzylchloride and then carefully with 0.4 ml of
1,2-dibromoethane. After start of the reaction, then the remaining amount
(19.4 ml) of the 2-chlorobenzylchloride, dissolved in 135 ml of absolute
diethyl ether, is instilled over 40 minutes, without the internal
temperature in the reaction vessel exceeding 30.degree. C. After formation
of the Grignard reagent is completed, the reaction mixture is cooled to
0.degree. C. and 5alpha,10alpha-epoxy-3,3-(2,2-dimethyltrimethylenedioxy)-
9(11)-estren-17beta-ol (15 g), dissolved in 80 ml of absolute
tetrahydrofuran, is slowly instilled. After stirring for one more hour at
ice-bath temperature, the reaction mixture is slowly warmed overnight to
room temperature and then poured onto diluted ammonium chloride solution.
The aqueous phase is repeatedly extracted with ethyl acetate. The combined
organic phases are washed neutral with sodium chloride solution, dried
with sodium sulfate and concentrated by evaporation in a vacuum. The
residue is chromatographed on aluminum oxide (neutral, stage III). 15.5 g
of the above compound is obtained.
b)
11beta,19-(4-Methoxy-o-phenylene)-3,3-(2,2-dimethyltrimethylenedioxy)-andr
ostane-5alpha,17beta-diol
600 ml of anhydrous ammonia, with exclusion of moisture, is condensed in
the reaction flask at -65.degree. C. and mixed with 970 mg of freshly cut
lithium chips. Immediately after the occurrence of the characteristic blue
coloring, a solution of 15 g of the product obtained under a) in 450 ml of
absolute tetrahydrofuran is instilled so that an interaction between
discoloring of the reaction solution and blue coloring occurs. After the
addition is completed, the excess lithium is eliminated by instillation of
ethanol, most of the ammonia is removed by evaporation and the reaction
mixture is poured onto water. The aqueous phase is extracted with ethyl
acetate. The combined organic phases are then washed with sodium chloride
solution, dried with sodium sulfate and concentrated by evaporation in a
vacuum. 13.9 g of crude product is isolated. Chromatography on aluminum
oxide (neutral, stage III) yields 11.6 g of the above compound.
[.alpha.].sub.D.sup.22 =+21.1.degree. (CHCl.sub.3); c=0.52)
Melting point: 223.degree.-224.degree. C. (diisopropyl ether)
c)
11beta,19-(4-Methoxy-o-phenylene)-5alpha-hydroxy-3,3-(2,2-dimethyltrimethy
lenedioxy)-androstan-17-one
14.2 g of chromium(III) oxide is added by portions to a mixture of 43.2 ml
of pyridine and 384 ml of methylene chloride at 0.degree. C. Then 11 g of
the steroid obtained according to b), dissolved in 75 ml of methylene
chloride, is slowly instilled at the same temperature into the reaction
mixture and the latter is stirred for 2 more hours at ice-bath
temperature. After the stirring is ended, the solid reaction components
are allowed to settle, the supernatant phase is decanted and the
precipitate is washed vigorously several times with methylene chloride.
The combined organic phases are freed of the remaining organic components
by washing with aqueous 0.5m potassium hydroxide solution, washed neutral
with water, dried on sodium sulfate and concentrated by evaporation in a
vacuum. 9 g of crude
11beta,19-(4-methoxy-o-phenylene)-5alpha-hydroxy-3,3-(2,2-dimethyltrimethy
lenedioxy)-androstan-17-one is isolated, whose purity is sufficient for
further reactions. 500 mg is purified by chromatography on aluminum oxide
(neutral, stage III) for analytical purposes. 443 mg of the desired
product is isolated as white foam.
[.alpha.].sub.D.sup.22 =+33.degree. (CHCl.sub.3 ; c=0.55)
Melting point: 235.degree.-238.degree. C.
EXAMPLE 2
17alpha-Hydroxy-17-(1-propinyl)-11beta-[4-(2-thiazolyl)-phenyl]-4beta-estra
-4,9-dien-3-one (28)
a)
3,3(2,2-Dimethyltrimethylenedioxy)-11beta-[4-(2-thiazolyl)phenyl]-9-estren
e-5alpha,17beta-diol (21)
13.4 g of magnesium chips under protective gas in 200 ml of absolute
tetrahydrofuran is taken and mixed with 3.5 ml of dibromoethane at
50.degree. C. After the reaction is completed, a solution of 97.8 g of
1-(chloro-4-(2-thiazolyl)-benzene (preparation according to literature:
Tetrahedron Letters 27, 4407 (1986)]in 250 ml of absolute tetrahydrofuran
is slowly instilled. It is stirred for 4 more hours at 70.degree. C. After
the reaction is completed, the Grignard solution is cooled to 0.degree. C.
and mixed with 1.43 g of copper(I) chloride. After 30 minutes, a solution
of 37.4 g of
5alpha,10alpha-epoxy-3,3-(2,2-dimethyltrimethylenedioxy)-9(11)-estren-17-o
l (EP-A 0 127 864) in 300 ml of absolute tetrahydrofuran is instilled.
After addition, the reaction mixture is stirred for 30 minutes more at
0.degree. C. and 15 minutes at room temperature and then poured onto ice
water. The aqueous phase is extracted with ethyl acetate, the organic
phases are combined and washed with saturated sodium chloride solution.
After drying on sodium sulfate and concentration by evaporation in a
vacuum, the resulting residue is chromatographed on aluminum oxide with a
mixture of ethyl acetate/hexane. 40.1 g of above compound 21 is obtained.
b)
3,3-(2,2-Dimethyltrimethylenedioxy)-5alpha-hydroxy-11beta-[4-(2-thizolyl)-
phenyl]-9-estren-17-one (22)
40.1 g of compound 21 produced under 2a is dissolved in 650 ml of toluene,
mixed with 20.1 g of aluminum isopropylate and 140 ml of cyclohexanone and
refluxed for 2 hours on a water separator. It is allowed to cool, about
400 ml of saturated sodium bicarbonate solution is instilled, and it is
suctioned off over Celite. The filtrate is washed (NaCl solution), dried
and concentrated by evaporation in a vacuum. The resulting residue is
chromatographed on aluminum oxide with a mixture of ethyl acetate/hexane.
25.9 g of above compound 22 is obtained.
c)
3,3-(2,2-Dimethyltrimethylenedioxy)-5alpha-hydroxy-11beta-[4-(2-thiazolyl)
-phenyl)-9-15-estradien-17-one (24)
Analogously to example 1a), 29.3 g of
3,3-(2,2-dimethyltrimethylenedioxy)-11beta-[4-(2-thiazolyl)-phenyl]-17-tri
methylsilyloxy-9,16-estradien-5alpha-ol (23) is obtained crude as yellowish
foam from 25.9 g of compound 22 produced under 2b, 145 mmol of
lithiumdiisopropylamide and 34.8 ml of chlorotrimethylsilane. This crude
product is suspended in 250 ml of absolute acetonitrile and mixed with
15.0 g of palladium(II) acetate. Working up takes place as described in
example la). 21.g of above compound 24 is isolated as crude product.
d)
3,3-(2,2-Dimethyltrimethylenedioxy)-5alpha-hydroxy-11beta-[4-(2-thiazolyl)
-phenyl]-14beta-estra-9,15-dien-17-one (25)
21.1 g of compound 24 produced under example 2c, dissolved in 2.0 l of
ethyl acetate, is mixed with 140 ml of triethylamine and stirred for 24
hours in the presence of 950 g of silica gel. After filtration, it is
concentrated by evaporation in a vacuum and the residue is chromatographed
on 2 kg of silica gel with a mixture of hexane/ethyl acetate/triethylamine
(80:19:1). 13.1 g of above compound 25 is obtained.
e)
3,3-(2,2-Dimethyltrimethylenedioxy)-5alpha-hydroxy-11beta-[4-(2-thiazolyl)
-phenyl)-14beta-estr-9-en-17-one (26)
A solution of 13.1 g of the compound produced under example 2d) in 450 ml
of ethanol is hydrogenated with 1.3 g of palladium/carbon (10% Pd).
Filtration over Celite and removal of the solvent in a vacuum yields,
after chromatography with hexane/ethyl acetate on aluminum oxide 9.3 g of
above compound 26.
f)
3,3-(2,2-Dimethyltrimethylenedioxy)-17beta-(1-propinyl)-11beta-[4-(2-thiaz
olyl)-phenyl)-14beta-estr-9-ene-5alpha,17alpha-diol (27)
200 ml of absolute tetrahydrofuran is saturated by 30 minutes introduction
of methylacetylene at 0.degree. C. Then 28.5 ml of a 1.6M solution of
n-butyllithium in hexane is instilled at 0.degree. to 5.degree. C., it is
stirred for 15 more minutes after the addition and then a solution of 1.23
g of the compound produced under example 2e) in 2o ml of absolute
tetrahydrofuran is instilled. The reaction mixture is stirred for 1 more
hour after the addition is completed, is poured onto ice water and the
aqueous phase is extracted with ethyl acetate. The combined organic phases
are dried on sodium sulfate and concentrated by evaporation in a vacuum.
The residue is chromatographed on aluminum oxide with a mixture of ethyl
acetate/hexane. 823 mg of above compound 27 is obtained.
g
823 mg of the compound produced under example 2f) is dissolved in 13 ml of
70% aqueous acetic acid and stirred for 1 hour at 50.degree. C. under
protective gas. After cooling, it is poured in ice water, neutralized by
addition of saturated sodium bicarbonate solution and extracted with ethyl
acetate. The combined organic phases are dried on sodium sulfate and
concentrated by evaporation in a vacuum. The residue is chromatographed
with a mixture of hexane/ethyl acetate on silica gel. 310 mg of title
compound 28 is isolated as white foam.
.sup.1 H-NMR (CDCl.sub.3)=Py.d.sub.5) .delta.: 0.91 (s; 3H, H--CH.sub.3),
1.89 (s; 3H, H--CH.sub.3), 4.5 (m; 1H, 11-H), 5.69 (s; 1H, 4-H), 7.30;
7.80 (in each case d, J=3Hz; 2H, --S--CH.dbd.CH--N) 7.50; 7.75 (AA'BB'
system, J=9Hz; HH, arH)
EXAMPLE 3
11beta-(4-Acetylphenyl)-17alpha-hydroxy-17(1-propinyl)-14beta-estra-4,9-die
n-3-one
750 mg of 11beta-{4-[1,1-(2,2-dimethyltrimethylenedioxy)ethyl]-phenyl}-
3,3-(2,2-dimethyltrimethylenedioxy)-17beta-(1-propinyl)-14beta-estr-9-ene-
5alpha,17alpha-diol is dissolved in 12 ml of 70% aqueous acetic acid and
stirred for 1 hour at 50.degree. C. under protective gas. After cooling,
it is poured into ice water, neutralized by addition of saturated sodium
bicarbonate solution and extracted with ethyl acetate. The combined
organic phases are dried on sodium sulfate and concentrated by evaporation
in a vacuum. The residue is chromatographed with a mixture of hexane/ethyl
acetate on silica gel. 300 mg of the title compound is isolated as white
foam.
[.alpha.].sub.D.sup.22 =242.degree. (CHCl.sub.3 ; c=0.500).
Production of the initial material takes place as follows:
a) Under protective gas, 10 ml of diisopropylamine in 290 ml of absolute
tetrahydrofuran at -10.degree. C. is taken and mixed with 50 ml of a 1.6m
n-butyllithium solution (hexane). It is stirred for a half hour more at
0.degree. C., then again cooled to -10.degree. C. and 13.6 g of
11beta-{4-[1,1-(2,2-dimethyltrimethylenedioxy)-ethyl]phenyl
}5alpha-hydroxy-3,3-(2,2-dimethyltrimethylenedioxy)-9-estren-17-one
(production according to European patent application 86101548.5,
publication No. 190759, example 6), dissolved in 150 ml of absolute
tetrahydrofuran is instilled. After the addition is completed, it is
stirred for 15 more minutes and then 17.2 ml of trimethylchlorosilane is
instilled. Then the reaction mixture is poured onto ice-cold saturated
sodium bicarbonate solution and the aqueous phase is extracted with ethyl
acetate. The combined organic phases are washed several times with
saturated ammonium chloride solution and concentrated by evaporation in a
vacuum. The residue is crystallized from 50 ml of acetonitrile. 13.2 g of
17-trimethylsilyloxy-11beta-{4-[1,1-(2,2-dimethyltrimethylenedioxy)-ethyl]
-phenyl}3,3-(2,2-dimethyltrimethylenedioxy)-9,16-estradien-5alpha-ol is
obtained.
b) 4.27 g of palladium(II) acetate in 150 ml of absolute acetonitrile is
taken and mixed with 12.12 g of the compound produced under a). The
reaction mixture is stirred for 16 hours at room temperature, then
filtered on silica gel and the filter residue is mixed well with methylene
chloride. The organic phase is concentrated by evaporation in a vacuum and
the residue chromatographed on silica gel. 10 g of
11beta-{4-[1,1-(2,2-dimethyltrimethylenedioxy)-ethyl]-phenyl}5alpha-hydrox
y-3,3-(2,2-dimethyltrimethylenedioxy)-9,15-estradien-17-one is isolated as
white foam.
c) 17.3 g of
11beta-{4-[1,1-(2,2-dimethyltrimethylenedioxy)ethyl]-phenyl}-3,3-(2,2-dime
thyltrimethylenedioxy)-5alpha-hydroxy-estra-9,15-dien-17-one, dissolved in
1.73 l of ethyl acetate, is mixed with 120 ml of triethylamine and stirred
for 24 hours in the presence of 800 g of silica gel. After filtration, it
is concentrated by evaporation in a vacuum and the residue is
chromatographed on 1.73 kg of silica gel with a mixture of hexane/ethyl
acetate/triethylamine (49:49:2). 10.4 g of
11beta-{4-[1,1-(2,2-dimethyltrimethylenedioxy)-ethyl]-phenyl}-3,3-(2,2-dim
ethyltrimethylenedioxy)-5alpha-hydroxy-14-beta-estra-9,15-dien-17-one is
obtained.
d) A solution of 3.0 g of the compound produced under 3c) in 150 ml of
ethanol is hydrogenated with 300 mg of palladium/carbon (10% Pd).
Filtration over Celite and removal of the solvent in a vacuum yields,
after chromatography with hexane/ethyl acetate on aluminum oxide 2.34 g of
11beta-{4-[1,1-(2,2-dimethyltrimethylenedioxy)-ethyl]-phenyl}-3,3-(2,2
-dimethyltrimethylenedioxy)-5alpha-hydroxy-14beta-estr-9-en-17-one.
Melting point: 145.degree.-148.degree. C.
e) 200 ml of absolute tetrahydrofuran is saturated by 30 minutes
introduction of methylacetylene at 0.degree. C. Then 28.5 ml of a 1.6M
solution of n-butyllithium in hexane is instilled 0.degree. C. to
5.degree. C., stirred for 15 more minutes after addition and then a
solution of 1.32 g of the compound produced under 3d) in 20 ml of absolute
tetrahydrofuran is instilled. The reaction mixture is stirred for 60
minutes more after the addition, is poured onto ice water and the aqueous
phase is extracted with ethyl acetate. The combined organic phases were
dried on sodium sulfate and concentrated by evaporation in a vacuum. The
residue is chromatographed on aluminum oxide (neutral, stage III) with a
mixture of ethyl acetate/hexane. 800 mg of
11beta-{4-[1,1-(2,2-dimethyltrimethylenedioxy)-ethyl]-phenyl}-3,3-(2,2-dim
ethyltrimethylenedioxy)-17beta(1-propinyl)-14beta-estr-9-ene-5alpha,17alpha
-diol is obtained.
.sup.1 H-NMR(CD.sub.2 Cl.sub.2) .delta.: 0.57 (s; 3H. H-CH.sub.3), 0.81 (s;
3H, H--CH.sub.3), 0.90 (s; 3H, H--CH.sub.3), 0.99 (s; 3H, 18-H), 1.22 (s:
3H, H--CH.sub.3), 1,48 (s: 3H, H--CH.sub.3), 1.91 (s: 3H, H--CH.sub.3).
EXAMPLE 4
11beta-(4-Acetylphenyl)-17alpha-hydroxy-17-(2-propinyl)14beta-estra-4,9-die
n-3-one
470 mg of
11beta-(4-Acetylphenyl)-17alpha-hydroxy-17-(3-trimethysilyl-2-propinyl)-14
beta-estra-4,9-dien-3-one in 24 ml of tetrahydrofuran is mixed with 2.35 ml
of a 1M solution of tetrabutylammonium fluoride in tetrahydrofuran and
stirred for 5 minutes at room temperature. It is poured on water and
extracted with ethyl acetate. The combined organic phases are washed with
water, dried on sodium sulfate and concentrated by evaporation. The
residue is chromatographed with a mixture of hexane/ethyl acetate on
silica gel. 280 mg of the title compound is isolated as foam.
[.alpha.].sub.D.sup.22 =166.degree. (CHCl.sub.3 : c=0.500).
Production of the initial material takes place as follows:
a) 13.6 ml of a 1.6M solution of n-butyllithium in hexane is instilled in a
solution of 2.33 g of 1-(trimethylsilyl)-1-propine in 100 ml of absolute
tetrahydrofuran at -5.degree. C. After addition, it is stirred for 1 hour
at this temperature, cooled to -78.degree. C. and then a solution of 1.20
g of the compound prepared under 3d) in 13 ml of tetrahydrofuran is
instilled. The reaction mixture is continued to be stirred overnight at
room temperature, poured onto ice water and the aqueous phase is extracted
with ethyl acetate. The combined organic phases are dried on sodium
sulfate and concentrated by evaporation. The residue is chromatographed
with a mixture of hexane/ethyl acetate on silica gel. 940 mg of
11beta-{4-[1,1-(2,2-dimethyltrimethylenedioxy)ethyl]-phenyl}-3,3-(2,2-dime
thyltrimethylenedioxy)-17-(3-trimethylsilyl-2-propinyl)-14beta-estr-9-ene-5
alpha,17alpha-diol is obtained as foam.
b) As described under example 3, 486 mg of
11beta-(4-acetylphenyl)-17alpha-hydroxy-(3-trimethylsilyl-2-propinyl)-14be
ta-estra-4,9-dien-3-one is obtained from 940 mg of the compound produced
under 4a) and 13 ml of 70% aqueous acetic acid.
[.alpha.].sub.D.sup.22 =150.degree. (CHCl3; c=0.500).
General Instructions 1 for the Production of the Compounds of General
Formula I" by Acid Cleavage of the Compounds of General Formula II (Table
1)
A solution of x g of steroid in y ml of acetone is mixed with z ml of 4N
hydrochloric acid and stirred a minutes at t.degree.C under argon. Then it
is poured on saturated sodium bicarbonate solution and extracted with
methylene chloride. The combined organic phases are washed with saturated
sodium chloride solution, dried on sodium sulfate and concentrated by
evaporation in a vacuum. By chromatography on silica gel with a mixture of
ethyl acetate/hexane, b g of the desired compound of general formula I' is
obtained from the crude product.
General Instructions 2 for the Production of the Compounds of General
Formula I' by Acid Cleavage of the Compounds of General Formula II (Table
2)
A solution of x g of steroid in y ml of 70% acetic acid is stirred for z
minutes at t.degree.C. Then it is poured on ice water, neutralized by
addition of aqueous ammonia solution and extracted with methylene
chloride. Analogously to the above working up, a g of the desired compound
of general formula I' is obtained.
EXAMPLE 5
17alpha-Hydroxy-17-(3-hydroxypropyl)-11beta,19-[4-vinyl-o-phenylene]-14beta
-androst-4-en-3-one (32) (Table 1)
a)
3,3-(2,2-Dimethyltrimethylenedioxy)-17-[3-tetrahydropryan-2-yloxy)-propyl]
-11beta,19-(4-tri-n-butylstannyl-o-phenylene)-14beta-androstane-5alpha,17al
pha-diol (29)
4.62 g of
3,3(2,2-dimethyltrimethylenedioxy)-17-[3-(tetrahydropyran-2-yloxy)-propyl]
-11beta,19-(4-trifluoromethylsulfonyloxy-o-phenylene)-14beta-androstane-5al
pha,17alpha-diol (compound 11, example 1f) is taken under protective gas in
160 ml of absolute dioxane, mixed with 9.7 ml of hexabutylditin, 290 mg of
tetrakis-(triphenylphosphine)palladium(O) and 810 mg of lithium chloride
and then refluxed for 30 minutes. After filtration over Celite it is
concentrated by evaporation in a vacuum and the residue is chromatographed
on aluminum oxide with a mixture of ethyl acetate/hexane. 5.7 g of the
above compound is obtained.
b)
3,3-(2,2-dimethyltrimethylenedioxy)-17-[3-(tetrahydropyran-2-yloxy)-propyl
]-11beta,19-(4-iodo-o-phenylene)-14beta-androstane-5alpha,17alpha-diol (30)
3.2 g of the compound produced under a) is dissolved in 80 ml of methylene
chloride and mixed by portions with 905 mg of iodine crystals at 0.degree.
C. under argon. After 30 minutes, the reaction mixture is washed with
saturated sodium thiosulfate and saturated sodium chloride solution. After
drying on sodium sulfate, concentration by evaporation in a vacuum and
column chromatographic purification on aluminum oxide, 1.9 g of the above
compound is obtained.
c)
3,3(2,2-Dimethyltrimethylenedioxy)-17-[3-(tetrahydropyran-2-yloxy)-propyl]
-11beta,19-(4-vinyl-o-phenylene)-14beta-androstane-5alpha,17alpha-diol (31)
Variant 1
1.9 g of the compound produced under b) under protective gas in 80 ml of
absolute toluene is taken, mixed with 1.03 g of tributylvinyltin and 298
mg of tetrakis-(triphenylphosphine)palladium(O) and refluxed for 30
minutes. After concentration by evaporation in a vacuum and purification
on silica gel, 480 mg of the above compound is obtained.
Variant 2
0.99 g of
3,3(2,2-dimethyltrimethylenedioxy)-17-[3-(tetrahydropyran-2-yloxy)-propyl]
-11beta,19-(4-trifluoromethylsulfonyloxy-o-phenylene)-14beta-androstane-5al
pha,17alpha-diol (11) is taken under protective gas in 20 ml of absolute
dimethylformamide, mixed with 0.54 g of tributylvinyltin, 158 mg of
tetrakis-(triphenylphosphine)palladium(O) and 113 mg of lithium chloride
and refluxed for 30 minutes. After concentration by evaporation in a
vacuum and purification on silica gel, 640 mg of the above compound is
obtained.
d
Title compound 32 is obtained according to the general instructions 1
(Table 1).
EXAMPLE 6
17alpha-Hydroxy-17-(3-hydroxypropyl)-11beta,19-(4-ethyl-o-phenylene)-14beta
-androst-4-en-3-one (34) (Table 1)
a)
3,3(2,2-Dimethyltrimethylenedioxy)-17-[3-(tetrahydropyran-2-yloxy)-propyl]
-11beta,19-(4-ethyl-o-phenylene)-14beta-androstane-5alpha,17alpha-diol (33)
640 mg of the compound produced under example 5c) in 50 ml of absolute
tetrahydrofuran is hydrogenated under normal pressure after addition of
140 mg of palladium/CaCO.sub.3 (5% Pd). After filtration over Celite and
column chromatographic purification on silica gel, 550 mg of above
compound 33 is isolated.
b
Title compound 34 is obtained according to general instructions 1 (Table
1).
EXAMPLE 7
17alpha-Hydroxy-17-(3-hydroxypropyl)-11beta,19-[4-(3-pyridyl)-o-phenylene]-
14beta-androst-4-en-3-one (36) (Table 1)
a)
3,3(2,2-Dimethyltrimethylenedioxy)-17-[3-(tetrahydropyran-2-yloxy)-propyl]
-11beta,19-[4-(3-pyridyl)-o-phenylene]-14beta-androstane-5alpha,17alpha-dio
l (35)
1.65 g of the compound produced under example 5a) is taken under protective
gas in 45 ml of absolute toluene, mixed with 2.9 g of 3-bromopyridine and
212 mg of tetrakis-(triphenylphosphine)palladium(O) and refluxed for 15
hours. After concentration by evaporation in a vacuum and purification on
silica gel, 800 mg of the above compound is obtained.
b
Title compound 36 is obtained according to the general instructions 1.
EXAMPLE 8
17alpha-Hydroxy-17-(3-hydroxypropyl)-11beta,19-[4-(3-thienyl)-o-phenylene]-
14beta-androst-4-en-3-one (38) (Table 1)
a)
3,3(2,2-Dimethyltrimethylenedioxy)-17-[3-(tetrahydropyran-2-yloxy)-propyl]
-11beta,19-[4-(3-furyl)-o-phenylene]- 14beta-androstane-5alpha,17alpha-diol
(37)
1.74 g of the compound produced under example 5a) is taken under protective
gas in 40 ml of absolute toluene, mixed with 3.15 g of 3-bromothiophene
and 224 mg of tetrakis(triphenylphosphine)palladium(O) and refluxed for 15
hours. After concentration by evaporation in a vacuum and purification on
silica gel, 720 mg of the above compound is obtained.
b
Title compound 38 is obtained according to the general instructions 1.
EXAMPLE 9
17alpha-Hydroxy-17-(3-hydroxypropyl)-11beta,19-(4-dimethylamino-o-phenylene
)-14beta-androst-4-en-3-one (51) (Table 1)
a)
3,3(2,2-Dimethyltrimethylenedioxy)-5alpha-hydroxy-11beta,19-(4-dimethylami
no-o-phenylene)-14beta-androsten-17-one (45)
18.6 g of
11beta,19-(4-dimethylamino-o-phenylene)-5alpha-hydroxy-3,3(2,2-dimethyltri
methylenedioxy)-androstan-17-one (42) (production of this initial compound
is described following example 9) is instilled in a solution of 109.4 mmol
of lithium diisopropylamide in 450 ml of absolute tetrahydrofuran,
dissolved in 150 ml of tetrahydrofuran, under protective gas at 0.degree.
C. Then chlorotrimethylsilane (26.4 ml) is instilled in the reaction
mixture. After stirring for 30 more minutes, the reaction solution is
poured onto ice-cold saturated sodium bicarbonate solution, the aqueous
phase is extracted with ethyl acetate and the organic phase is washed with
water and saturated ammonium chloride solution. After drying on sodium
sulfate, the organic phase is concentrated by evaporation in a vacuum.
20.1 g of
3,3(2,2-dimethyltrimethylenedioxy)-11beta,19-(4-dimethylamino-o-phenylene)
-17-trimethylsilyloxy-16-androsten-5alpha-ol (43) is isolated crude as
yellowish foam. This crude product is suspended in 250 ml of absolute
acetonitrile and mixed with 11.6 g of palladium(II) acetate. After
stirring for 12 more hours at room temperature, the reaction mixture is
suctioned off over Celite, the filter residue is rewashed with ethyl
acetate, the filtrate is concentrated by evaporation in a vacuum and the
residue is filtered over silica gel (grain size 0.2-0.5 mm). After
concentration of the filtrate by evaporation, 7.0 g of
3,3(2,2-dimethyltrimethylenedioxy)-5alpha-hydroxy-11beta,
19-(4-dimethylamino-o-phenylene)-15-androsten-17-one (44) is obtained
crude as yellowish foam. This crude product is dissolved in 1 liter of a
mixture of hexane/ethyl acetate (1:9), mixed with 72 ml of triethylamine
and stirred for 72 hours in the presence of 400 g of silica gel. After
filtration, it is concentrated by evaporation and the residue is
chromatographed on 800 g of silica gel with a mixture of hexane/ethyl
acetate/triethylamine (80:19:1). 5.36 g of above compound 45 is obtained
as a 1st fraction. 0.93 g of a mixture (3:1, according to TLC) of 44 and
above compound 45 is eluted as 2nd fraction.
b)
3,3(2,2-Dimethyltrimethylenedioxy)-5alpha-hydroxy-11beta,19-(4-dimethylami
no-o-phenylene)- 14beta-androstan-17-one (47)
6.01 ml of diisopropylamine in 180 ml of absolute tetrahydrofuran is taken
under protective gas at -10.degree. C. and is mixed with 29.5 ml of a 1.6M
n-butyllithium solution (hexane). It is stirred for 30 more minutes at
-5.degree. C. and then 3.1 g of compound 45, produced under a), dissolved
in 50 ml of absolute tetrahydrofuran, is instilled. The reaction mixture
is stirred for 15 more minutes at -5.degree. C. and then mixed by
instillation with 10.0 ml of trimethylchlorosilane. After 15 minutes it is
cooled to -70.degree. C. and 5.2 ml of hydrogen fluoride-pyridine complex
is instilled. Then the reaction mixture is stirred for 10 more hours at
-30.degree. C. and then poured onto saturated sodium bicarbonate solution.
The aqueous phase is extracted with ethyl acetate, washed (NaCl solution),
dried on sodium sulfate and concentrated by evaporation in a vacuum. 3.0 g
of
3,3(2,2-dimethyltrimethylenedioxy)-5alpha-hydroxy-11beta,19-(4-dimethylami
no-o-phenylene)-14beta-androst-4-en-17-one (46) is obtained crude as
yellowish foam. This crude product is dissolved in 120 ml of
tetrahydrofuran/ethanol (1:1) and hydrogenated with 500 mg of
palladium/calcium carbonate (5% Pd). Filtration over Celite and removal of
the solvent in a vacuum yields, after chromatography with hexane/ethyl
acetate on silica gel, 2.4 g of above compound 47.
c)
3,3(2,2-Dimethyltrimethylenedioxy)-11beta,19-(4-dimethylamino-o-phenylene)
-17-[3-(tetrahydropyran-2-yloxy)-1propinyl]-14beta-androstane-5alpha,17alph
a-diol (48)
The lithium organic compound is produced from 9.94 g of
3-(tetrahydropyran-2-yloxy)-1-propine in 170 ml of absolute
tetrahydrofuran and 45.0 ml of a 1.6M solution of n-butyllithium (hexane)
at -10.degree. C. and a solution of 2.40 g of compound 47 obtained under
b) in 45 ml of absolute tetrahydrofuran is instilled therein at
-10.degree. C. It is stirred first for 1 hour at 0.degree. C., then
overnight at room temperature. It is poured into ice water and extracted
with ethyl acetate. The crude product is chromatographed on neutral
aluminum oxide with hexane/ethyl acetate. As main fraction 2.14 g of above
compound 48 is obtained as white foam.
d)
3,3(2,2-Dimethyltrimethylenedioxy)-11beta,19-(4-dimethylamino-o-phenylene)
-17-[3-(tetrahydropyran
2-yloxy)propyl]-14beta-androstane-5alpha,17alpha-diol (49)
As described under b), 1.79 g of above compound 49 is obtained, after
hydrogenation, from 2.14 g of compound 48, produced under c), in 140 ml of
ethanol/tetrahydrofuran (1:1) and 430 mg of palladium/calcium carbonate
(5% Pd).
e)
17-(3-Hydroxypropyl)-17alpha,5alpha-dihydroxy-11beta,19-(4-dimethylamino-o
-phenylene)-14beta-androst-4-en-3-one (50)
1.77 g of compound 49 produced under d), is dissolved in 90 ml of acetone
and mixed with 4.4 ml of 4N hydrochloric acid. After stirring for 16 hours
at 0.degree. C., the reaction mixture is poured onto saturated sodium
bicarbonate solution and the aqueous phase is extracted with methylene
chloride. The combined organic phases are dried on sodium sulfate and
concentrated by evaporation in a vacuum. The residue is chromatographed on
silica gel. 0.98 g of above compound 50 is obtained.
.sup.1 H-NMR (CDCl.sub.3) .delta.:0.55 (3H,s,18-H); 2.93(6H,s,NMe.sub.2);
3.68(2H,m,CH.sub.2 OH); 6.4-7.3(3H,3m, protons on the aromatic substance)
f
0.98 g of compound 50 produced under e) is dissolved in 50 ml of acetone
and mixed with 2.5 ml of 4N hydrochloric acid. After stirring for 4 more
hours at 25.degree. C., it is worked up as described under e). 0.67 g of
title compound 51 is obtained.
Production of Initial Compound (42)
11beta,19-(4-Dimethylamino-o-phenylene)-5alpha-hydroxy-3,3(2,2-dimethyltrim
ethylenedioxy)-androstan-17-one
a)
19-(4-Dimethylamino-2-chlorophenyl)-3,3(2,2-dimethyl-trimethylenedioxy)-9(
11)-androstene-5alpha,17beta-diol (40)
7.72 g of magnesium chips are taken at room temperature under protective
gas in 50 ml of absolute diethyl ether and mixed with 0.7 ml of
1,2-dibromoethane. After the start of the reaction, 64.5 g of
2-chloro-5-dimethylamino-benzylchloride, dissolved in 700 ml of absolute
diethyl ether, is then instilled over 40 minutes without the internal
temperature in the reaction vessel exceeding 30.degree. C. After the
formation of the Grignard reagent is completed,
5alpha,10alpha-epoxy-3,3(2,2-dimethyltrimethylenedioxy)-9(11)-estren-17bet
a-ol (23.6 g), dissolved in 200 ml of absolute tetrahydrofuran, is slowly
instilled. After stirring for 1 more hour at ice-bath temperature, it is
stirred overnight and then poured onto dilute ammonium chloride solution.
The aqueous phase is extracted several times with ethyl acetate. The
combined organic phases are washed neutral with sodium chloride solution,
dried with sodium sulfate and concentrated by evaporation in a vacuum. The
residue is chromatographed on aluminum oxide (neutral, step III). 33.0 g
of the above compound is obtained.
b)
11beta,19-(4-Dimethylamino-o-phenylene)-3,3(2,2-dimethyltrimethylenedioxy)
-androstane-5alpha,17beta-diol (41)
790 ml of anhydrous ammonia, with exclusion of moisture, is condensed in
the reaction vessel at -65.degree. C. and mixed with 2.91 g of freshly cut
lithium chips. Immediately after occurrence of the characteristic blue
coloring, a solution of 33 g of the product obtained under a) in 2000 ml
of absolute tetrahydrofuran is instilled so that an interaction between
discoloring of the reaction solution and blue coloring occurs. After the
addition is completed, the excess lithium is eliminated by instillation of
ethanol, most of the ammonia is removed by evaporation and the reaction
mixture is poured onto water. The aqueous phase is extracted with ethyl
acetate. The combined organic phases are then washed with sodium chloride
solution, dried with sodium sulfate and concentrated by evaporation in a
vacuum. 31.5 g of crude product is isolated. Chromatography on silica gel
yields 20.0 g of the above compound.
c)
11beta,19-(4-Dimethylamino-o-phenylene)-5alpha-hydroxy-3,3(2,2-dimethyltri
methylenedioxy)-androstan-17-one (42)
20.3 g of aluminum-tri-isopropanolate and 147 ml of cyclohexanone are added
to 25.1 g of the compound produced under b) in 1000 ml of toluene. It is
refluxed for 1.5 hours and about 250 ml is continuously distilled off. The
reaction mixture is mixed with saturated sodium bicarbonate solution,
suctioned off through Celite, washed neutral (sodium chloride solution)
and concentrated by evaporation. Chromatography on aluminum oxide with
hexane/ethyl acetate yields 18.6 g of initial product 42.
EXAMPLE 10
11beta,19-(4-Dimethylamino-o-phenylene)-4',5'-dihydrospiro[14beta-androst-4
-ene-17alpha,2'-(3'H)-furan-3-one (52)
404 mg of compound 51 produced under example 9) is dissolved in 20 ml of
methylene chloride and mixed with 1.2 ml of triethylamine. The mixture is
cooled to 0.degree. C. and 500 mg of p-toluenesulfonic acid chloride is
added. After 60 minutes at 0.degree. C. and refluxing for another 6 hours,
the reaction mixture is poured onto saturated sodium bicarbonate solution,
the aqueous phase is extracted with methylene chloride, the combined
organic phases are washed with saturated sodium chloride solution, dried
(sodium sulfate) and concentrated by evaporation in a vacuum. After
chromatography of the crude product on silica gel, 370 mg of title
compound 52 is isolated.
[.alpha.].sub.D.sup.22 =124.0.degree. (CHCl.sub.3 ; c=0.515)
EXAMPLE 11
11beta,19-(4-dimethylamino-o-phenylene)-17alpha-hydroxy-17(3-hydroxy-propyl
)-14beta-androsta-I,4-dien-3-one (55)
a)
11beta,19-(4-Dimethylamino-o-phenylene)-17alpha-trimethylsilyloxy-17-(3-tr
imethylsilyloxypropyl)-3-trimethylsilyloxy-14beta-androsta-2,4-diene (53)
1.5 g of compound 51 prepared according to example 9f), dissolved in 45 ml
of absolute tetrahydrofuran, is instilled in a solution of 33 mmol of
lithium diisopropylamide in 150 ml of absolute tetrahydrofuran under argon
at 0.degree. C. Then, trimethylchlorosilane (7.95 ml) is instilled in the
reaction mixture. After stirring for 45 minutes, the reaction solution is
poured onto cold saturated sodium bicarbonate solution, the aqueous phase
is extracted with ethyl acetate and the organic phase is successively
washed with water and saturated ammonium chloride solution. After drying
on sodium sulfate, it is concentrated by evaporation in a vacuum. 2.48 g
of the silyldienol ether 53 is obtained as crude product.
b)
11beta,19-(4-Dimethylamino-o-phenylene)-17alpha-trimethylsilyloxy-17-(3-tr
imethylsilyloxypropyl)-14beta-androsta-1,4-dien-3-one (54)
2.48 g of the silyldienol ether prepared under a) is suspended as crude
product in 30 ml of absolute acetonitrile and mixed with 1 g of
palladium(II) acetate. After stirring for 1 more hour at room temperature,
the reaction mixture is suctioned off over Celite and the filtrate is
concentrated by evaporation in a vacuum. 2.31 g of the above dienone 54 is
obtained as crude product.
c
2.31 g of the dienone produced under b) is dissolved in 30 ml of absolute
methanol and mixed with 2.3 g of anhydrous potassium carbonate. The
mixture is stirred for 1 more hour at room temperature under protective
gas, then poured onto saturated sodium chloride solution and extracted
several times with methylene chloride. The combined organic phases are
washed with saturated sodium chloride solution, dried on sodium sulfate
and concentrated by evaporation in a vacuum. Chromatography of the residue
on silica gel with a mixture of ethyl acetate/hexane results in 510 mg of
title compound 55.
.sup.1 H-NMR(CDCl.sub.3 +Py x d.sub.5) .delta.: 0.57(3H,s,18-H);
2.92(6H,s,NMe); 3.70 (2H,m,CH.O-H); 6.14(1H,s,4-H); 6.15(1H,d,J=10Hz,2-H);
7.00 (1H,d,J=10Hz,l-H); 6.4-7.3(3H,3m,protons on the aromatic substance)
EXAMPLE 12
11beta,19-(4-Dimethylamino-o-phenylene)-17alpha-hydroxy-17-(1-propinyl)-14b
eta-androsta-4,6-dien-3-one (59)
a) 11beta,19-(4-Dimethylamino-o-phenylene)-14beta-androst-4-en-3,17-dione
(56)
4.1 g of above enone 56 is obtained from 6.0 g of compound 47 described
under example 9b) in 300 ml of acetone and 15 ml of 4N hydrochloric acid
according to the general instructions 1 after 5 hours of stirring at room
temperature.
b)
11beta,19-(4-Dimethylamino-o-phenylene)-3-ethoxy-14beta-androsta-3,5-dien-
17-one (57)
4.1 g of the product obtained under a) is taken in a mixture of 100 ml of
absolute methylene chloride, 9 ml of ethanol and 10 ml of orthoformic acid
triethyl ester and mixed with 1.9 g of p-toluenesulfonic acid
(monohydrate) at 0.degree. C. Then it is stirred for 3 more hours at
ice-bath temperature, then mixed with an excess of sodium bicarbonate
solution and the aqueous phase is extracted with methylene chloride. After
washing (sodium chloride solution) and drying (sodium sulfate) of the
organic phases, it is concentrated by evaporation in a vacuum.
Crystallization from ethanol (about 10 ml) yields 1.7 g of the above
compound.
c)
11beta,19-(4-Dimethylamino-o-phenylene)-3-ethoxy-17-(prop-1-inyl)-14beta-a
ndrosta-3,5-dien-17alpha-ol (58)
150 ml of absolute tetrahydrofuran is saturated at 0.degree. C. with
propine. Then 1.6 of M n-butyllithium solution (hexane) (28.8 ml) is
slowly instilled in this solution. It is stirred for 30 more minutes and a
solution of 1.7 g of the product prepared under b) in 29 ml of absolute
tetrahydrofuran is instilled in the reaction mixture. After stirring for
30 more minutes, it is poured onto water, extracted with ethyl acetate and
the combined organic phases are washed with sodium chloride solution.
After drying (sodium sulfate), concentration by evaporation in a vacuum
and chromatography on aluminum oxide (neutral, step III), 0.99 g of the
above compound is obtained.
d
0.99 g of the product obtained according to c) is taken in 100 ml of
methylene chloride at -50.degree. C. and mixed with 0.34 ml of
triethylamine and then with 409 mg of N-bromosuccinimide. It is stirred
for 30 more minutes at -40.degree. C., then poured onto sodium sulfate
solution and extracted several times with methylene chloride. After drying
on sodium sulfate, concentration by evaporation in a vacuum and
chromatography on silica gel, 240 mg of slightly impure
11beta,19-(4-dimethylamino-o-phenylene)-17alpha-hydroxy-17-(1-propinyl)-6b
eta-bromo-14beta-androst-4-en-3-one is isolated. After dissolving of the
product in 3 ml of absolute dimethylformamide, 91 mg of lithium bromide
and 57 mg of lithium carbonate are added under argon and stirred for 1
hour at 100.degree. C. After cooling of the reaction mixture to room
temperature, it is poured onto water, neutralized with 4N hydrochloric
acid, cooled to 0.degree. C., stirred for one more hour at this
temperature and the precipitated steroid is suctioned off. Chromatography
on silica gel with hexane/ethyl acetate yields 170 mg of title compound
59.
.sup.1 H-NMR(CDCl.sub.3 +Py x d.sub.5) .delta.: 0.55(3H,s,18-H),
1.90(3H,s,Me);2.90(6H,s,NMe.sub.2);
5.75(1H,s,4-H);6.15-6.25(2H,m,6-H,7-H); 6.4-7.3(3H,3m,protons on the
aromatic substance)
EXAMPLE 13
11beta,19-(4-Dimethylamino-o-phenylene)-17alpha-hydroxy-17alpha-methyl-17-(
1-propinyl)-14beta-androst-4-en-3-one (60)
A Grignard solution is prepared in the usual way from 90 mg of magnesium
chips and 0.23 ml of methyl iodide in 4 ml of absolute ether. After
addition of 19 mg of copper(I) chloride at 0.degree. C. it is stirred for
30 more minutes and then a solution of 150 mg of product 59 prepared under
example 12d) in 2 ml of absolute tetrahydrofuran is instilled. It is
stirred for 2 hours at 0.degree. C., poured onto saturated ammonium
chloride solution, extracted with ethyl acetate, washed with dilute
ammonia solution and then with saturated sodium chloride solution, dried
and concentrated by evaporation in a vacuum. After chromatography of the
crude product on silica gel, 36 mg of above title compound 60 is isolated.
PG,73
.sup.1 H-NMR(CDCl.sub.3 +Py x d.sub.5) .delta.:0.56(3H,s,18-H);
0.90(3H,d,J=7Hz, 7alpha-Me); 1.90 (3H,s,Me); 2.92 (6H,s,NMe.sub.2); 5.82
(1H,s,4-H); 6.4-7.3(3H,3m,protons on the aromatic substance)
EXAMPLE 14
17alpha-Hydroxy-17-(3-hydroxyprop-(Z)-1-enyl)-11beta-[4-(3-pyridyl)-phenyl]
-14beta-estra-4,9-dien-3-one (69) (Table 2)
a)
3,3(2,2-Dimethyltrimethylenedioxy)-11beta-[4-(3-pyridyl)phenyl]-9-estrene-
5alpha,17beta-diol (61)
10.6 g of above compound 61 is obtained, as described under example 2a),
from 3.57 g of magnesium chips in 150 ml of absolute tetrahydrofuran, 3.2
g of 1-bromo-4-(3-pyridyl)-benzene [preparation following example 14] in
100 ml of absolute tetrahydrofuran, 380 mg of copper(I) chloride and 10.0
g of
5alpha,10alpha-epoxy-3,3(2,2-dimethyltrimethylenedioxy)-9(11)-estren-17-ol
in 80 ml of absolute tetrahydrofuran.
b)
3,3(2,2-Dimethyltrimethylenedioxy)-5alpha-hydroxy-11beta-[4-(3-pyridyl)-ph
enyl]-9-estren-17-one (62)
6.82 g of above compound 62 is obtained, as described under example 2b),
from 10.6 g of compound 61 prepared under a) in 180 ml of toluene, 5.26 g
of aluminum isopropylate and 36.6 ml of cyclohexanone.
c)
3,3(2,2-Dimethyltrimethylenedioxy)-5alpha-hydroxy-11beta-[4-(3-pyridyl)-ph
enyl]-9,15-estradien-17-one (64)
7.5 g of
3,3(2,2-dimethyltrimethylenedioxy)-11beta-[4-(3-pyridyl-phenyl]-17-trimeth
ylsilyloxy-9,16-estradien-5alpha-ol (63) is obtained, as described under
example 2c), raw from 6.82 g of compound 62 prepared under b), 38 mmol
lithium diisopropylamide and 9.06 ml chlorotrimethylsilane. Analogous
reaction with 3.9 g of palladium(II) acetate yields, after working up,
5.60 g of above compound 64.
d)
3,3(2,2-Dimethyltrimethylenedioxy)-5alpha-hydroxy-11beta-[4-(3-pyridyl)-ph
enyl]-14beta-estra-9,15-dien-17-one (65)
3.2 g of above compound 65 is obtained, as described under example 2d), is
obtained from 5.60 g of compound 64 prepared under c), 600 ml of ethyl
acetate, 40 ml of triethylamine and 250 g of silica gel, after
chromatography on 550 g of silica gel.
e)
3,3(2,2-Dimethyltrimethylenedioxy)-5alpha-hydroxy-11beta-[4-(3-pyridyl)-ph
enyl]-14beta-estr-9en-17-one (66)
A solution of 3.39 g of compound 65, produced under d), in 155 ml of
ethanol is hydrogenated with 0.68 g of palladium/calcium carbonate (5%
Pd). Filtration on Celite and removal of the solvent in a vacuum yields,
after chromatography with hexane/ethyl acetate on aluminum oxide, 2.62 g
of above compound 66.
f)
3,3(2,2-Dimethyltrimethylenedioxy)-17-[3-tetrahydropyran-2-yloxy)-1-propin
yl]-11beta-[4-(3-pyridyl)-phenyl]-14beta-estr-9-en-5alpha,17alpha-diol (67)
2.3 g of above compound 67 is obtained, after column chromatography, as
described under example 9c), from 6.95 g of
3-(tetrahydropyran-2-yloxy)-1-propine in 245 ml of absolute
tetrahydrofuran, 31 ml of a 1.6M solution of n-butyllithium (hexane) and
2.62 g of compound 66, produced under e), in 53 ml of tetrahydrofuran.
g)
3,3(2,2-Dimethyltrimethylenedioxy)-17-[3-(tetrahydropyran-2-yloxy)-prop-(Z
)-1-enyl]-11beta-[4-(3-pyridyl)-phenyl]-14beta-estr-9-ene-5alpha,17alpha-di
ol (68)
900 mg of compound 67 produced under f) is dissolved in 10 ml of ethanol
and mixed with 0.9 ml of pyridine and 90 mg of palladium/barium sulfate
(10% Pd). Then it is hydrogenated with hydrogen at normal pressure. After
absorption of an equivalent of hydrogen, the catalyst is separated by
filtration over Celite, the filtrate is concentrated by evaporation and
the residue is chromatographed on aluminum oxide with a mixture of ethyl
acetate/hexane. 700 mg of above compound 68 is isolated.
h
Title compound 69 is obtained according to general instructions 2 (Table
2).
Preparation of the Aryl Bromide
4-(3-pyridyl)-phenol
26.8 g of 4-bromophenol was taken under protective gas in 1000 ml of
dioxane, mixed with 90 g 3-tributylstannylpyridine [preparation according
to litt.: Org. Magn. Resonance, 7 (1975), 610] and 11.1 g of
bis-(triphenylphosphine)-palladium(II) chloride and refluxed for 15 hours.
After concentration by evaporation in a vacuum and purification on silica
gel, 15.92 g of the above compound is isolated.
4-(3-Pyridyl)-1-trifluoromethylsulfonyloxy)-benzene
15.92 g of the above compound and 55.0 g of 4-dimethylaminopyridine are
taken under argon at -78.degree. C. in 900 ml of methylene chloride and
mixed with 19.8 ml of trifluoromethanesulfonic acid anhydride, dissolved
in 300 ml of absolute methylene chloride, by instillation. After 30
minutes, the reaction mixture is poured onto saturated sodium bicarbonate
solution. After another 30 minutes, it is extracted with methylene
chloride, the organic phases are washed with sodium chloride solution,
dried on sodium sulfate and concentrated by evaporation in a vacuum. After
chromatography on silica gel, 26.0 g of the above compound is isolated.
4-(3-Pyridyl)-1-tri-n-butylstannyl-benzene
21.4 g of the above compound is obtained, as described under example 5a),
after column chromatographic purification on aluminum oxide, from 26.0 g
of the above compound in 1300 ml of dioxane, 127.8 ml of hexabutylditin,
10.72 g of lithium chloride and 3.84 g of tetrakis-(triphenylphosphine)-
palladium.
1-Bromo-4-(3-pyridyl)-benzene
21.4 g of the above compound in 220 ml of carbon tetrachloride is mixed, by
instillation, with 2.44 ml of bromine with vigorous stirring at
-40.degree. C. under argon. It is allowed to come to room temperature,
washed with sodium chloride solution, dried on sodium sulfate and
concentrated by evaporation in a vacuum. After chromatography on aluminum
oxide, 10.2 g of the above compound is isolated.
EXAMPLE 15
11beta-[4-(3-Pyridyl)-phenyl]-17alpha-hydroxy-17-(3-hydroxypropyl)-14beta-e
stra-4,9-dien-3-one (71) (Table 2)
a)
3,3(2,2-Dimethyltrimethylenedioxy)-17-[3-(tetrahydropyran-2-yloxy)-propyl]
-11beta-[4-(3-pyridyl)-phenyl]-14beta-estr-9-ene-5alpha,17alpha-diol (70)
632 mg of above compound 70 is obtained, after pressure hydrogenation (60
bars, room temperature) and the usual working up, from 1.4 g of compound
67 prepared under example 14f) in 57 ml of ethanol and 140 mg of
palladium/carbon (10% Pd).
b
Title compound 71 is obtained according to general instructions 2 (Table
2).
EXAMPLE 16
11beta-(4-(3-Pyridyl)-phenyl)-14beta-estra-4,9-dien-(17alpha,1'-spiro-17,2'
)-tetrahydrofuran-3-one (72)
135 mg of title compound 72 is obtained, as described under example 10),
from 175 mg of compound 71 prepared under example 15) in 10 ml of
methylene chloride, 0.5 ml of triethylamine and 206 mg of
p-toluenesulfonic acid chloride.
[.alpha.].sub.D.sup.22 =201.0.degree. (CHCl.sub.3 ; c=0.505)
TABLE 1
______________________________________
Ex- Reaction
am- Batch Parameters Yield
ple x[g] y[ml] z[ml]
t[.degree.C.]
a[min]
b[g] [.alpha.].sub.D.sup.20 CHCL.sub.3
)
______________________________________
5 0.48 30 1.2 50 30 0.26 125.4(c = 1.87)
Steroid 5d (31) Steroid Bsp. 5 (32)
6 0.55 30 1.4 45 60 0.26 106.0(c = 0.52)
Steroid 6b (33) Steroid Bsp. 6 (34)
7 0.76 40 1.9 50 120 0.34 157.4(c = 0.51)
Steroid 7b (35) Steroid Bsp. 7 (36)
8 0.72 40 1.9 50 30 0.33 161.5(c = 0.52)
Steroid 8b (37) Steroid Bsp. 8 (38)
9 0.98 50 2.5 25 240 0.67 134.5(c = 0.52)
Steroid 9F (50) Steroid Bsp. 9 (51)
______________________________________
TABLE 2
______________________________________
Reaction
Exam- Batch Parameters Yield
ple c[g] y[ml] t[.degree.C.
z[min]
a[g] [.alpha.].sub.D.sup.22 (CHCl.sub.3)
______________________________________
14 0.70 9 50 60 0.33 253.5(c = 0.52)
Steroid 14h (68) Steroid Bsp. 14 (69)
15 0.63 8 50 60 0.35 222.6(c = 0.2)
Steroid 15b (70) Steroid Bsp. 15 (71)
______________________________________
Bsp. = example
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